Grafted polymer and use thereof

ABSTRACT

A grafted glycosaminoglycan polymer is disclosed. The grafted glycosaminoglycan polymer comprises a glycosaminoglycan having a polymer backbone and one or more side chains comprising a polyalkylene glycol-containing residue grafted onto the polymer backbone.

PRIORITY CLAIM

The present application is a divisional application of co-pending U.S.Ser. No. 17/022,398, filed Sep. 16, 2020, which claims priority to U.S.Provisional Patent Application Ser. No. 62/903,206, entitled “GraftedPolymer and Use Thereof,” filed Sep. 20, 2019, the contents of eachbeing incorporated by reference herein in their entirety.

BACKGROUND

The present invention generally relates to a grafted polymer and itsuse.

It is highly desirable that a contact lens be as comfortable as possiblefor wearers. Manufacturers of contact lenses are continually working toimprove the comfort of the lenses. Nevertheless, many people who wearcontact lenses still experience dryness or eye irritation throughout theday and particularly towards the end of the day. An insufficientlywetted lens at any point in time will cause significant discomfort tothe lens wearer. Although wetting drops can be used as needed toalleviate such discomfort, it would certainly be desirable if suchdiscomfort did not arise in the first place.

Glycosaminoglycans (GAGs) are a group of polysaccharides built ofrepeating disaccharide units. Due to high polarity and water affinity,they can be found in many systems of human and animal bodies. Forexample, GAGs occur on the surface of cells and in the extracellularmatrix of animal organisms such as skin, cartilage, and lungs.

GAGs each have a chemical structure including a repeating basaldisaccharide structure consisting of uronic acid and hexosamine andbeing optionally sulfated to various degrees. GAGs are mainlyclassified, depending on the disaccharides constituting them, into threegroups: a first group of compounds composed of chondroitin sulfate ordermatan sulfate, a second group of compounds composed of heparansulfate or heparin, and a third group of hyaluronic acid compounds. Forexample, the compounds composed of chondroitin sulfate or dermatansulfate consist of a disaccharide: uronic acid (glucuronic acid oriduronic acid) (β1→3) N-acetylgalactosamine, the compounds composed ofheparan sulfate or heparin consist of a disaccharide: uronic acid(glucuronic acid or iduronic acid) (β1→4) N-acetylglucosamine, and thehyaluronic acid consists of a disaccharide: glucuronic acid (β1→3)N-acetylglucosamine. In addition, the structure is highly diverse due toa combination with modification by sulfation.

These GAGs are known as important biological materials having bothphysicochemical properties derived from characteristic viscoelasticityand biological properties mediated by interactions with variousfunctional proteins, depending on the molecular size and the sulfationpattern.

It would be desirable to provide improved GAGs that can make abiomedical device such as a contact lens as comfortable as possible forthe wearer and exhibit suitable physical and chemical properties, e.g.,lubriciousness and wettability.

SUMMARY

In accordance with one exemplary embodiment, a grafted glycosaminoglycanpolymer is provided comprising a glycosaminoglycan having a polymerbackbone and one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the polymer backbone.

In accordance with a second exemplary embodiment, a crosslinkedpolymeric network is provided comprising a reaction product of one ormore grafted glycosaminoglycan polymers comprising a glycosaminoglycanhaving a polymer backbone and one or more side chains comprising apolyalkylene glycol-containing residue grafted onto the polymerbackbone, and one or more crosslinking agents.

In accordance with a third exemplary embodiment, a crosslinked polymericnetwork is provided comprising a reaction product of one or moreglycosaminoglycans having a polymer backbone comprising one or morereactive functional groups, one or more polymers comprising polyalkyleneglycol chains and at least one reactive end group or a salt thereof andone or more crosslinking agents.

In accordance with a fourth exemplary embodiment, a biomedical devicehaving a coating on a surface thereof is provided, the coatingcomprising one or more grafted glycosaminoglycan polymers comprising aglycosaminoglycan having a polymer backbone and one or more side chainscomprising a polyalkylene glycol-containing residue grafted onto thepolymer backbone.

In accordance with a fifth exemplary embodiment, a packaging system forthe storage of an ophthalmic device is provided comprising a sealedcontainer containing one or more unused ophthalmic devices immersed inan aqueous packaging solution comprising one or more graftedglycosaminoglycan polymers comprising a glycosaminoglycan having apolymer backbone and one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the polymer backbone, wherein theaqueous packaging solution has an osmolality of at least about 200mOsm/kg, a pH of about 6 to about 9 and is steam sterilized.

In accordance with a sixth exemplary embodiment, a method of preparing apackage comprising a storable, sterile ophthalmic device is provided,the method comprising: (a) immersing an ophthalmic device in an aqueouspackaging solution comprising one or more grafted glycosaminoglycanpolymers comprising a glycosaminoglycan having a polymer backbone andone or more side chains comprising a polyalkylene glycol-containingresidue grafted onto the polymer backbone, wherein the aqueous packagingsolution has an osmolality of at least about 200 mOsm/kg and a pH in therange of about 6 to about 9; (b) packaging the aqueous packagingsolution and the ophthalmic device in a manner preventing contaminationof the device by microorganisms; and (c) steam sterilizing the packagedsolution and the ophthalmic device.

In accordance with a seventh exemplary embodiment, an aqueous ophthalmiccomposition is provided comprising one or more grafted glycosaminoglycanpolymers comprising a glycosaminoglycan having a polymer backbone andone or more side chains comprising a polyalkylene glycol-containingresidue grafted onto the polymer backbone, wherein the aqueousophthalmic composition has an osmolality in a range from about 200mOsmol/kg to about 500 mOsmol/kg.

In accordance with an eighth exemplary embodiment, a gel composition forpromoting wound healing is provided wherein the gel compositioncomprises one or more grafted glycosaminoglycan polymers comprising aglycosaminoglycan having a polymer backbone and one or more side chainscomprising a polyalkylene glycol-containing residue grafted onto thepolymer backbone.

In accordance with a ninth exemplary embodiment, a wound dressing isprovided comprising a gel composition comprising one or more graftedglycosaminoglycan polymers comprising a glycosaminoglycan having apolymer backbone and one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the polymer backbone.

The grafted glycosaminoglycan polymers and/or crosslinked polymericnetworks described in exemplary embodiments herein advantageouslyexhibit suitable physical and chemical properties, e.g., oxygenpermeability, lubriciousness, mucoadhesivity and wettability, forprolonged contact with the body by grafting a polyalkyleneglycol-containing residue onto a reactive functional group in thepolymer backbone of the glycosaminoglycan. The grafted glycosaminoglycanpolymers and/or crosslinked polymeric networks are believed toadvantageously exhibit less enzymatic, oxidative and thermal degradationand thus higher stability, longer shelf life and rigidity of desiredconformation. In addition, the grafted glycosaminoglycan polymers and/orcrosslinked polymeric networks are further believed to advantageouslyexhibit antibiofouling, anti-protein deposition and antimicrobialactivity for prolonged contact with the body.

The grafted glycosaminoglycan polymers and/or crosslinked polymericnetworks described in exemplary embodiments herein may advantageouslyprovide improved lubricity to the surface of a biomedical device such asa contact lens. For example, the benefits of improved lubricity usingthe grafted glycosaminoglycan polymers and/or crosslinked polymericnetworks include minimizing interactions between a contact lens and itsrespective packaging blister, a lens surface that is more robust towardprocessing and handling conditions, and improved comfort upon insertioninto a subject's eye, as well as reduced deposition (e.g., protein,lipid, etc.) and thus potentially reducing biofilm formation by thecontact lens wearer onto the lens surface.

In addition, the grafted glycosaminoglycan polymers and/or crosslinkedpolymeric networks described in exemplary embodiments hereinadvantageously provide improved wettability to the surface of abiomedical device such as a contact lens. It is believed that thebenefits of having improved wettability using the graftedglycosaminoglycan polymers of the present invention include, forexample, delaying evaporation of the aqueous layer of the device due toits effect like-coating on the ocular surface and moisturizingproperties and thus potentially relieving dry eye symptoms.

Further, the grafted glycosaminoglycan polymers and/or crosslinkedpolymeric networks described in exemplary embodiments hereinadvantageously provide improved stability as well as increased shelflife of a packaging solution when combined with one or more comfortagents.

DETAILED DESCRIPTION

The illustrative embodiments described herein are directed to graftedglycosaminoglycan polymers and/or crosslinked polymeric networks usefulin, for example, treating the surface of a biomedical device intendedfor direct contact with body tissue or fluid, packaging solutions in apackaging system for the storage of an ophthalmic device, aqueousophthalmic compositions, gel compositions and wound dressings. Ingeneral, the grafted glycosaminoglycan polymer comprises aglycosaminoglycan (GAG) having a polymer backbone and one or more sidechains comprising a polyalkylene glycol-containing residue grafted ontothe polymer backbone. A GAG is one molecule with many alternatingsubunits. In general, GAGs are represented by the formula A-B-A-B-A-B,where A is an uronic acid and B is an amino sugar that may or may not beeither O- or N-sulfated, where the A and B units can be heterogeneouswith respect to epimeric content or sulfation. Any natural or syntheticpolymer containing uronic acid can be used. Other GAGs are sulfated atdifferent sugars. There are many different types of GAGs having commonlyunderstood structures such as, for example, chondroitin sulfate (e.g.,chondroitin 4- and 6-sulfates), heparan, heparin sulfate, heparosan,dermatan, dermatan sulfate, hyaluronic acid or a salt thereof, e.g.,sodium hyaluronate or potassium hyaluronate, keratan sulfate, and otherdisaccharides such as sucrose, lactulose, lactose, maltose, trehalose,cellobiose, mannobiose and chitobiose. Glycosaminoglycans can bepurchased from Sigma, and many other biochemical suppliers such as HTLBiotechnology (France). In one illustrative embodiment, the GAG ishyaluronic acid. In one embodiment, the GAG is chondroitin sulfate.

The GAGs will have a reactive functional group in the polymer backbonefor grafting the polyalkylene glycol-containing residue including thepolyalkylene glycol derivatives. Suitable reactive functional groups inthe polymer backbone include carboxylate-containing groups,hydroxyl-containing groups, silicone hydride groups, sulfur-containinggroups such as thiols and other groups including polymerizablefunctionalities such as allylic, vinylic, acrylate, methacylate,methacrylamide etc. In addition, the sugar rings of the GAGs can beopened to form aldehydes for further functionalization. The GAGs for useherein can have a weight average molecular weight ranging from about10,000 to about 3,000,000 Daltons (Da) in which the lower limit is fromabout 10,000, about 20,000, about 30,000, about 40,000, about 50,000,about 60,000, about 70,000, about 80,000, about 90,000, or about100,000, and the upper limit is about 200,000, about 300,000, about400,000, about 500,000, about 600,000, about 700,000, about 800,000,about 900,000, about 1,000,000, or about up to 2,800,000 Da, where anyof the lower limits can be combined with any of the upper limits.

Hyaluronic acid is a well-known, naturally occurring, water solublebiodegradable polymer composed of two alternatively linked sugars,D-glucuronic acid and N-acetylglucosamine, linked via alternatingβ-(1,4) and β-(1,3) glycosidic bonds. Hyaluronic acid is a non-sulfatedGAG. The polymer is hydrophilic and highly viscous in aqueous solutionat relatively low solute concentrations. It often occurs naturally asthe sodium salt, sodium hyaluronate. Methods of preparing commerciallyavailable hyaluronan and salts thereof are well known. Hyaluronan can bepurchased from Seikagaku Company, Clear Solutions Biotech, Inc.,Pharmacia Inc., Sigma Inc., and many other suppliers HTL Biotechnology,Contipro and Bloomage Biotechnology Corporation. Hyaluronic acid hasrepeating units of the structure represented by the following formula:

Accordingly, the repeating units in hyaluronic acid can be as follows:

In general, hyaluronic acid or a salt thereof can have from about 2 toabout 1,500,000 disaccharide units. In one embodiment, hyaluronic acidor a salt thereof can have a weight average molecular weight rangingfrom about 10,000 to about 3,000,000 Da in which the lower limit is fromabout 10,000, about 20,000, about 30,000, about 40,000, about 50,000,about 60,000, about 70,000, about 80,000, about 90,000, or about100,000, and the upper limit is about 200,000, about 300,000, about400,000, about 500,000, about 600,000, about 700,000, about 800,000,about 900,000, about 1,000,000, or about up to 2,800,000 Da, where anyof the lower limits can be combined with any of the upper limits.

Chondroitin sulfate is a linear sulfated polysaccharide composed ofrepeating β-D-glucuronic acid (GlcA) and N-acetyl-β-D-galactosamine(GalNAc) units arranged in the sequence by GlcA-β(1,3)-GalNAc-β(1,4)glycosidic bonds. In one embodiment, chondroitin sulfate has one or morerepeating units of the structure represented by the following formula:

In one illustrative embodiment, chondroitin sulfate has repeating unitsof the structure represented by the following formula:

In general, chondroitin sulfate can have from about 2 to about 1,500,000repeating units. In one embodiment, chondroitin sulfate can have aweight average molecular weight ranging from about 10,000 to about3,000,000 Da in which the lower limit is from about 5,000, 10,000, about20,000, about 30,000, about 40,000, about 50,000, about 60,000, about70,000, about 80,000, about 90,000, or about 100,000, and the upperlimit is about 200,000, about 300,000, about 400,000, about 500,000,about 600,000, about 700,000, about 800,000, about 900,000, about1,000,000, or about 3,000,000 Da where any of the lower limits can becombined with any of the upper limits or any of the upper limits can becombined with any of the upper limits.

In one illustrative embodiment, dermatan sulfate has repeating units ofthe structure represented by the following formula:

In general, dermatan sulfate can have from about 2 to about 1,500,000repeating units. In one embodiment, chondroitin sulfate can have aweight average molecular weight ranging from about 10,000 to about3,000,000 Da in which the lower limit is from about 5,000, 10,000, about20,000, about 30,000, about 40,000, about 50,000, about 60,000, about70,000, about 80,000, about 90,000, or about 100,000, and the upperlimit is about 200,000, about 300,000, about 400,000, about 500,000,about 600,000, about 700,000, about 800,000, about 900,000, about1,000,000, or about 3,000,000 Da where any of the lower limits can becombined with any of the upper limits or any of the upper limits can becombined with any of the upper limits.

In one illustrative embodiment, heparin and heparin sulfate hasrepeating units of the structure represented by the following formula:

In general, heparin and heparin sulfate can have from about 2 to about1,500,000 repeating units. In one embodiment, chondroitin sulfate canhave a weight average molecular weight ranging from about 10,000 toabout 3,000,000 Da in which the lower limit is from about 5,000, 10,000,about 20,000, about 30,000, about 40,000, about 50,000, about 60,000,about 70,000, about 80,000, about 90,000, or about 100,000, and theupper limit is about 200,000, about 300,000, about 400,000, about500,000, about 600,000, about 700,000, about 800,000, about 900,000,about 1,000,000, or about 3,000,000 Da where any of the lower limits canbe combined with any of the upper limits or any of the upper limits canbe combined with any of the upper limits.

In one illustrative embodiment, keratan sulfate has repeating units ofthe structure represented by the following formula:

In general, keratan sulfate can have from about 2 to about 1,500,000repeating units. In one embodiment, chondroitin sulfate can have aweight average molecular weight ranging from about 10,000 to about3,000,000 Da in which the lower limit is from about 5,000, 10,000, about20,000, about 30,000, about 40,000, about 50,000, about 60,000, about70,000, about 80,000, about 90,000, or about 100,000, and the upperlimit is about 200,000, about 300,000, about 400,000, about 500,000,about 600,000, about 700,000, about 800,000, about 900,000, about1,000,000, or about 3,000,000 where any of the lower limits can becombined with any of the upper limits or any of the upper limits can becombined with any of the upper limits.

The polyalkylene glycol-containing residue grafted onto a reactivefunctional group in the polymer backbone of the GAG is derived from apolymer comprising polyalkylene glycol chains and at least one reactiveend group or a salt thereof (e.g., HCl). The polyalkylene glycol chainscan range from 2 to 10,000 subunits or from 2 to 5000 subunits. In oneembodiment, the polyalkylene glycol chains comprise a structure:—((CH₂)_(a)—O)_(b)— where “a” is from 2 to 6 or from 2 to 4 and “b” isfrom 2 to 10,000 or from 2 to 5000. In one illustrative embodiment, apolyalkylene glycol is one or more of polyethylene glycol chains such as(e.g., —(CH₂CH₂O)_(b)—) (i.e. PEG), polypropylene glycol chains (e.g.,—(CH₂CH₂CH₂O)_(b)—), polybutylene glycol chains (e.g.,—(CH₂CH₂CH₂CH₂O)_(b)—), ethylene oxide-propylene oxide chains, andethylene oxide-butylene oxide chains.

The at least one reactive end group includes a reactive functional groupcapable of grafting on to the reactive functional group in the polymerbackbone of the GAG. Suitable reactive functional groups include, forexample, a halogen, amino groups, aldehyde groups, carboxylic acidgroups, alcohol groups, thiol groups, hydrazide groups, glycidyl groups,etc. These groups are attached to the polymeric compound by way of alinker group “X”. Examples of reactive functional groups include—X-PDMS-NH₂ where PDMS is polydimethylsiloxane having a number molecularweight ranging from about 100 to about 150,000 Da, —X—OH, —X—NH₂, —X—SH,and —X—C(O)—R′ where R′ is hydrogen or an organic hydrocarbyl moietycomprised of 1-20 carbon atoms such as lower alkyl group (e.g., methyl,ethyl, propyl, etc.) or benzyl.

Suitable linker groups “X” for attaching the reactive functional endgroup to the polymer include, for example, any of the following: —C(O)—,—N—C(O)—NH—CH₂—, —N—C(O)—NH—CH₂—CH₂—, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—,—C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—C(O)—NH—,—C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—,—C(O)—NH—CH₂—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—CH₂—,—CH₂—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—,—CH₂—CH₂—CH₂—(Si—O—Si)_(n)—O—Si—CH₂—CH₂—CH₂— where n=3 to 100 andcombinations of two or more of any of the foregoing.

The other end group can be either an inert end-capping group or areactive end-group. An inert end-capping group is one that does notreadily undergo chemical transformation under typical synthetic reactionconditions. A reactive end group can be used for further cross-linking.Suitable end-capping groups include, for example, an alkoxy group, ahydroxyl group, a thiol group, an amine group and an ethylenicallypolymerizable group such as, for example, an acrylate or methacrylategroup. An alkoxy group is represented by the general formula —OR, whereR is an organic moiety comprised of 1-20 carbon atoms such as loweralkyl group (e.g., methyl or ethyl) or benzyl. R however may besaturated or unsaturated, and includes aryl, heteroaryl, cyclo,heterocyclo, and substituted forms of any of the foregoing. Forinstance, an end-capped PEG can comprise the structure RO—(CH₂CH₂O)_(n)—where R is as defined above. In one illustrative embodiment, suitableend groups include, by way of example, —OCH₃, —OCH₂CH₃, —OCH₂(C₆H₅),—NH₂, —OH, and —SH.

The polymers comprising polyalkylene glycol chains and at least onereactive end group or a salt thereof for use in the invention includepolymers having a variety of molecular weights, structures or geometries(e.g., branched, linear, and the like). In an illustrative embodiment,the weight average molecular weight of a polymer comprising polyalkyleneglycol chains and at least one reactive end group or a salt thereof mayrange from about 100 Da to about 10,000 Da. For example, in oneillustrative embodiment, the weight average molecular weight of apolymer comprising polyalkylene glycol chains and at least one reactiveend group or a salt thereof can be greater than about 100 Daltons, orgreater than about 250 Da, or greater than about 500 Da, or greater thanabout 750 Da, or greater than about 1,000 Da, or greater than about2,000 Da, or greater than about 5,000 Da, or greater than about 7,500Da. In another illustrative embodiment, the weight average molecularweight of a polymer comprising polyalkylene glycol chains and at leastone reactive end group or a salt thereof can be less than about 10,000Da, or less than about 7,500 Da, or less than about 5,000 Da, or lessthan about 2,000 Da, or less than about 1,000 Da, or less than about 750Da, or less than about 600 Da. As one skilled in the art can appreciate,any molecular weight between those listed above can be used.

The foregoing polymers are either commercially available from varioussources such as BroadPharm, Sigma, JenKem, and Advanced PolymerMaterials Inc. or can be prepared according to methods well known in theart.

In one illustrative embodiment, a polymer comprising polyalkylene glycolchains and at least one reactive end group or a salt thereof is apolymer or a salt thereof having the following structure:

Z—(((CH₂)_(a)—O)_(b))_(c)—Y

wherein Z is an end-capped group, Y is reactive functional group, a isfrom 2 to 6, b is from 2 to 10,000 and c is 1 or 2.

Z is an end-capped (or end-capping) group which can be an inert group ora reactive group present on a terminus of the polymeric compound such asa polyethylene glycol (PEG) polymer. Suitable end-capping groups includeany of those discussed above.

Y is a reactive functional group capable of grafting on to the reactivefunctional group in the polymer backbone of the GAG. Suitable reactivefunctional groups include any of those discussed above. Suitable linkergroups “X” for attaching the reactive functional group any of thosediscussed above.

The polymer compounds may be derived from a polyalkylene glycol. Ingeneral, a polyalkylene glycol comprises the following structure:—((CH₂)_(a)—O)_(b)— where “a” is from 2 to 6 or from 2 to 4 and “b” isfrom 2 to 10,000 or from 2 to 5000. In one illustrative embodiment, apolyalkylene glycol is one or more of a polyethylene glycol (e.g.,—(CH₂CH₂O)_(b)—), a polypropylene glycol (e.g., —(CH₂CH₂CH₂O)_(b)—) apolybutylene glycol (e.g., —(CH₂CH₂CH₂CH₂O)_(b)—), ethyleneoxide-propylene oxide, and ethylene oxide-butylene oxide. Thepolyalkylene glycols for use in the invention include polyalkyleneglycols having a variety of molecular weights, structures or geometries(e.g., branched, linear, and the like) as discussed above.

In one embodiment, representative examples of polymers for use hereininclude any of the following:

wherein n is from 2 to 10,000.

The grafted glycosaminoglycan polymers disclosed herein can be obtainedby grafting the reactive functionality of the one or more polymerscomprising polyalkylene glycol chains onto the reactive functionality inthe polymer backbone of the glycosaminoglycan. For example, in oneillustrative embodiment, an amine reactive end group of the polymercomprising polyalkylene glycol chains can be grafted onto a carboxylicacid group in the polymer backbone of the glycosaminoglycan. The graftpolymerization reaction can obtain a degree of grafting, i.e., thenumber of sidechains in the polymer backbone containing the polyalkyleneglycol-containing residue, ranging from about 5 to about 100%. In oneillustrative embodiment, the degree of grafting can range from about 10to about 90%. In one illustrative embodiment, the degree of grafting canrange from about 20 to about 80%.

In one illustrative embodiment, the grafting reaction can be carried outby reacting the glycosaminoglycan with the polymer under suitablegrafting conditions using a catalyst system such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysuccinimide(NHS) or EDC/hydroxybenzotriazole (HOBt) coupling at a pH of about 6.8with about 1 to about 5 weight percent dissolved solids in water to formrandom copolymers or block copolymers.

In one illustrative embodiment, a glycosaminoglycan can be added to thereaction in an amount ranging from about 0.05 wt. % to about 10 wt. %.In one illustrative embodiment, a glycosaminoglycan can be added to thereaction in an amount ranging from about 0.5 wt. % to about 5 wt. %.

In one embodiment, a polymer comprising polyalkylene glycol chains canbe added to the reaction in an amount ranging from about 0.01 wt. % toabout 20 wt. %. In one illustrative embodiment, a polymer comprisingpolyalkylene glycol chains can be added to the reaction in an amountranging from about 0.10 wt. % to about 0.5 wt. %.

The grafting reaction is ordinarily carried out in the presence of acatalyst system. In some embodiments, the catalyst system is acarbodiimide catalyst system such as, for example, EDC. In someembodiments, a co-catalyst is used with the carbodiimide catalystsystem. Suitable co-catalysts include, for example, HOBt, NHS andsulfo-N-hydroxysuccinimide (Sulfo-NHS). In some embodiments, thecatalyst system includes EDC/NHS. In one embodiment, the EDC is added tothe reaction in an amount ranging from about 0.01 wt. % to about 20 wt.%. In one embodiment, the NHS is added to the reaction in an amountranging from about 0.01 wt. % to about 20 wt. %.

In another embodiment, the grafting reaction is carried out by reactingthe glycosaminoglycan with monomers capable of forming a polymercomprising polyalkylene glycol chains and at least one reactive endgroup or a salt thereof in-situ. For example, the reaction can becarried out by first forming a solution containing at least theglycosaminoglycan and cocatalyst system. Next, the glycosaminoglycan isactivated by adding an activator to the solution. A suitable activatorincludes, for example, one or more epoxyamines. Epoxyamines aremolecules that generally include both at least one amine moiety (e.g., aprimary, secondary, tertiary, or quaternary amine) and at least oneepoxide moiety. The epoxyamine compound can be a monoepoxyamine compoundand or a polyepoxyamine compound, i.e., an epoxyamine containing one ormore amine groups and one or more epoxide groups. In one embodiment, asuitable epoxyamine compound is one in which the amine moiety is linkedto the epoxide moiety by way of a C₁ to C₃₀ alkylene group. Suitableepoxyamine compounds include, for example, epoxyethylamine,epoxypropylamine, epoxybutylamine, epoxyamyl amine and the like. Theactivation reaction can be carried out at a suitable temperature and fora time period to react the activator with the glycosaminoglycan, e.g.,at room temperature and a time period ranging from about 10 hours toabout 48 hours. In one embodiment, an epoxyamine can be added toreaction mixture in an amount ranging from about 0.01 to about 50 wt. %.

After the activator has been reacted with the glycosaminoglycan, themonomers capable of forming in-situ a polymer comprising polyalkyleneglycol chains and at least one reactive end group or a salt thereof areadded to the reaction mixture. In one embodiment, the monomers include apolyol and an epoxy alcohol. Suitable polyols include, for example oneor more diols. Representative diols include, by way of example, a C₂ toC₁₂ diol such as ethylene glycol, propylene glycol, 1,3-propanediol,1,2-butanediol, 1,4-butanediol, 2-methyl-1,3-propanediol, poloxamer 407and the like. The epoxyalcohol compound can be a monoepoxyalcoholcompound and or a polyepoxyalcohol compound, i.e., an epoxyalcoholcontaining one or more alcohol groups and one or more epoxide groups. Inone embodiment, a suitable epoxyalcohol compound is one in which thealcohol moiety is linked to the epoxide moiety by way of a C₁ to C₃₀alkylene and or alkyne group. Suitable epoxyalcohol compounds include,for example, glycidyl alcohol, 3-oxiranyl-2-Propen-1-ol,3-(2-oxiranyl)2-propen-1-ol, 1-(2,3-dihydroxypropyl)4-(2-oxiranylmethyl) ester of 2-butenedioic acid, 1-(2-hydroxyethyl)2-(2-oxiranylmethyl) ester of 1,2-benzenedicarboxylic acid.

In general, the polyol and epoxyalcohol can be added sequentially orsimultaneously to the reaction mixture. In one embodiment, the polyol isadded to the reaction mixture and reacted with the activatedglycosaminoglycan, followed by the epoxyalcohol to form the polyalkyleneglycol-containing residue. The reaction can be carried out at a suitabletemperature and for a time period for the completion of the reaction tomaximize the yield of the product polyalkylene glycol residue onto thepolymer backbone of the glycosaminoglycan, e.g., at room temperature anda time period ranging from about 10 hours to about 48 hours. In oneembodiment, a polyol can be added to reaction mixture in an amountranging from about 0.01 to about 50 wt. %, and an epoxyalcohol can beadded to reaction mixture in an amount ranging from about 0.01 to about50 wt. %.

The resulting grafted glycosaminoglycan polymer can be a randomcopolymer or a block copolymer. In one illustrative embodiment, agrafted glycosaminoglycan polymer disclosed herein can have a weightaverage molecular weight ranging from about 20,000 to about 6,000,000 Dain which the lower limit is from about 20,000, about 30,000, about40,000, about 50,000, about 60,000, about 70,000, about 80,000, about90,000, or about 100,000 Da, and the upper limit is about 200,000, about300,000, about 400,000, about 500,000, about 600,000, about 700,000,about 800,000, about 900,000, about 1,000,000, about 2,000,000, about3,000,000, about 4,000,000, about 5,000,000 or up to about 6,000,000 Da.

In another embodiment, a crosslinked polymer network can be formed byeither reacting the foregoing grafted glycosaminoglycan polymers withone or more crosslinking agents, or adding one or more crosslinkingagents to the grafting reaction mixture. The crosslinking agents for useherein can be any suitable crosslinking agent known in the art. Ingeneral, a suitable crosslinking agent is, for example, a crosslinkingagent having complimentary functional groups to the graftedglycosaminoglycan polymers. In one embodiment, a suitable crosslinkingagent includes, for example, a bi- or polyfunctional crosslinking agent.The bi- or polyfunctional crosslinking agent comprises two or morefunctional groups capable of reacting with functional groups of thegrafted glycosaminoglycan polymers resulting in the formation ofcovalent bonds.

Suitable bi- or polyfunctional crosslinking agents include, for example,divinyl sulfone, diepoxides, multiepoxides, dihydrazides, dihydricalcohols, polyhydric alcohols, polyhydric thiols, anhydrides,carbodiimides, polycarboxylic acids, carboxymethyl thiols, cysteine, andcysteine-like amino acids and the like. In one embodiment, a bi- orpolyfunctional crosslinking agent is a bi- or polyepoxide, such asdiglycidyl ether derivatives. According to an embodiment, the bi- orpolyfunctional epoxide crosslinking agent comprises two or more glycidylether functional groups. The glycidyl ether functional groups react withprimary hydroxyl groups of the hyaluronic acid and the chondroitinsulfate, resulting in the formation of ether bonds. In one embodiment,suitable bi- or polyfunctional crosslinking agents include, for example,1,4-butanediol diglycidyl ether (BDDE),1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidylether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane,1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether,polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidylether, polyglycerol polyglycidyl ester, diglycerol polyglycidyl ether,glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether,pentaerythritol polyglyglycidyl ether, sorbitol polyglycidyl ether,1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritoltetraglycidyl ether, polyepoxides and the like.

Suitable dihydrazide crosslinking agents include, for example, succinicacid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide,pimelic acid dihydrazide, suberic acid dihydrazide, azalaic aciddihydrazide, sebacic acid dihydrazide, undecanedioic acid dihydrazide,dodecanedioic acid dihydrazide, brassylic acid dihydrazide,tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide,thapsic acid dihydrazide, octadecanedioic acid dihydrazide and the like.

Suitable dihydric alcohol crosslinking agents include, for example,ethylene glycol, propylene glycol, butylene glycol diethylene glycol,dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol,pentylene glycol, heptylene glycol, octylene glycol and the like.Suitable polyhydric alcohol crosslinking agents include, for exampleglycerin, pentaerythrite, xylitol, galactitol and the like. Suitablecarbodiimide coupling agents include, for example, a compound of formulaX—N═C═N—X, wherein each X independently is a C₁ to C₆ alkyl optionallysubstituted with 1-2 dialkylamino groups, or is a C₅ to C₆ cycloalkylgroup, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodimidehydrochloride, and cyclohexyl carbodiimide. Suitable anhydridecrosslinking agents include, for example, methacrylic anhydride,succinic anhydride and the like. In one embodiment, a suitablecrosslinking agent is an aldehyde crosslinking agent such as, forexample, formaldehyde, gluteraldehyde, glutaraldehyde and the like. Inone embodiment, a suitable crosslinking agent includes, for example,polyethylene glycol diacrylates, polyethylene glycol diamines, ureas,diisocyanates and the like.

In one embodiment, a crosslinked polymeric network described inexemplary embodiments herein can be obtained by forming a solution ofthe one or more grafted glycosaminoglycan polymers and adding one ormore of the foregoing crosslinking agents. In one embodiment, acrosslinked polymeric network described in exemplary embodiments hereincan be obtained by adding one or more of the foregoing crosslinkingagents to the grafting solution of the one or more glycosaminoglycanpolymers and one or more polymers. The solution is stirred for asuitable time sufficient to crosslink the reaction mixture. In oneembodiment, the crosslinking can take place between 1° C. and about 99°C. over a time period of about 2 hours to about 48 hours.

The solution can contain a suitable solvent such as, for example, water,crown-ethers, dimethyl sulphoxide (DMSO), dimethyl formamide (DMF) andother aprotic solvents. The pH of the solution can be adjusted ifnecessary by adding, for example, a hydroxide such as sodium hydroxide.In general, the crosslinking agent can be added to the solution in anamount ranging from about 0.01 wt. % to about 10 wt. %, based on thetotal weight of the solution. When crosslinking the graftedglycosaminoglycan polymer, the amount of the grafted glycosaminoglycanpolymer can range from about 0.010 wt. % to about 50 wt. %, based on thetotal weight of the solution. In one embodiment, the amount of thegrafted glycosaminoglycan polymer can range from about 0.01 wt. % toabout 5 wt. %, based on the total weight of the solution.

In one embodiment, one or more glycosaminoglycans can be added to thereaction of the grafted glycosaminoglycan polymers and one or morecrosslinking agents to form a crosslinked polymeric network, i.e., tocrosslink the grafted glycosaminoglycan polymers with the one or moreglycosaminoglycans. In general, the one or more glycosaminoglycans canbe any of the glycosaminoglycans discussed hereinabove. In oneembodiment, the one or more glycosaminoglycans are hyaluronic acid. Inone embodiment, the one or more glycosaminoglycans are chondroitinsulfate. In one embodiment, the one or more glycosaminoglycans includehyaluronic acid and chondroitin sulfate. In one illustrative embodiment,the amount of the one or more glycosaminoglycans can range from about0.010 wt. % to about 50 wt. %, based on the total weight of thesolution. In one embodiment, the amount of the one or moreglycosaminoglycans can range from about 0.01 wt. % to about 5 wt. %,based on the total weight of the solution.

The one or more crosslinking agents will have complimentary functionalgroups to the grafted glycosaminoglycan polymer and to theglycosaminoglycan. For example, a suitable crosslinking agent such as abi- or polyfunctional crosslinking agent connects the graftedglycosaminoglycan polymer with the glycosaminoglycan, and further actsas a spacer between the grafted glycosaminoglycan polymer and theglycosaminoglycan.

It will be readily understood and appreciated by those skilled in theart that the reaction product constitutes a complex mixture of compoundsincluding, for example, the grafted glycosaminoglycan polymercrosslinked with the glycosaminoglycan, the grafted glycosaminoglycanpolymer crosslinked with the grafted glycosaminoglycan polymer, theglycosaminoglycan crosslinked with the glycosaminoglycan, unreactedgrafted glycosaminoglycan polymer and unreacted glycosaminoglycan. Forexample, in one illustrative embodiment, a grafted glycosaminoglycanpolymer crosslinked with a glycosaminoglycan can have a weight averagemolecular weight ranging from about 20,000 to about 6,000,000 Da inwhich the lower limit is from about 20,000, about 30,000, about 40,000,about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, orabout 100,000 Da, and the upper limit is about 200,000, about 300,000,about 400,000, about 500,000, about 600,000, about 700,000, about800,000, about 900,000, about 1,000,000, about 2,000,000, about3,000,000, about 4,000,000, about 5,000,000 or up to about 6,000,000 Dawhere any of the lower limits can be combined with any of the upperlimits. It is not necessary to isolate one or more specific componentsof the reaction product mixture. Indeed, the reaction product mixturecan be employed as is. If necessary, any excess crosslinker can beremoved by dialysis or precipitation in ethanol.

In one illustrative embodiment, a biomedical device is provided whichcomprises one or more of the grafted glycosaminoglycan polymers and/orone or more of the crosslinked polymeric networks described herein attheir surfaces. The grafted glycosaminoglycan polymer and/or crosslinkedpolymeric network may be provided over the entire surface of thebiomedical device or over only a portion of the biomedical devicesurface. The grafted glycosaminoglycan polymer and/or crosslinkedpolymeric network may also be provided within the construct of thebiomedical device. As used herein, the term “biomedical device” shall beunderstood to mean any article that is designed to be used while eitherin or on mammalian tissues or fluid, and preferably in or on humantissue or fluids. Representative examples of biomedical devices include,but are not limited to, artificial ureters, diaphragms, intrauterinedevices, heart valves, catheters, denture liners, prosthetic devices,ophthalmic lens applications, where the lens is intended for directplacement in or on the eye, such as, for example, intraocular devicesand contact lenses. In one illustrative embodiment, the biomedicaldevices are ophthalmic devices, particularly contact lenses, and mostparticularly contact lenses made from silicone hydrogels.

As used herein, the term “ophthalmic device” refers to devices thatreside in or on the eye. These devices can provide optical correction,wound care, tissue repair, drug delivery, diagnostic functionality orcosmetic enhancement or effect or a combination of these properties.Useful ophthalmic devices include, but are not limited to, ophthalmiclenses such as soft contact lenses, e.g., a soft, hydrogel lens; soft,non-hydrogel lens and the like, hard contact lenses, e.g., a hard, gaspermeable lens material and the like, intraocular lenses, overlaylenses, ocular inserts, optical inserts, viscoelastics and the like. Asis understood by one skilled in the art, a lens is considered to be“soft” if it can be folded back upon itself without breaking.

The biomedical devices to be surface modified according to the presentinvention can be any material known in the art capable of forming abiomedical device as described above. In one embodiment, a biomedicaldevice includes devices formed from material not hydrophilic per se.Such devices are formed from materials known in the art and include, byway of example, polysiloxanes, perfluoropolyethers, fluorinatedpoly(meth)acrylates or equivalent fluorinated polymers derived, e.g.,from other polymerizable carboxylic acids, polyalkyl (meth)acrylates orequivalent alkylester polymers derived from other polymerizablecarboxylic acids, or fluorinated polyolefins, such as fluorinatedethylene propylene polymers, or tetrafluoroethylene, preferably incombination with a dioxol, e.g., perfluoro-2,2-dimethyl-1,3-dioxol.Representative examples of suitable bulk materials include, but are notlimited to, Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon,Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon orTeflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which arecopolymers of about 63 to about 73 mol % ofperfluoro-2,2-dimethyl-1,3-dioxol and about 37 to about 27 mol % oftetrafluoroethylene, or of about 80 to about 90 mol % ofperfluoro-2,2-dimethyl-1,3-dioxol and about 20 to about 10 mol % oftetrafluoroethylene.

In another embodiment, a biomedical device includes a device formed frommaterial hydrophilic per se, since reactive groups, e.g., carboxy,carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium or hydroxygroups, are inherently present in the material and therefore also at thesurface of a biomedical device manufactured therefrom. Such devices areformed from materials known in the art and include, by way of example,polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinylpyrrolidone (PVP), polyacrylic acid, polymethacrylic acid,polyacrylamide, polydimethylacrylamide (DMA), polyvinyl alcohol and thelike and copolymers thereof, e.g., from two or more monomers selectedfrom hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinylpyrrolidone, acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, vinyl alcohol and the like. Representative examples ofsuitable bulk materials include, but are not limited to, Polymacon,Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon,Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Perfilcon,Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon, Atlafilcon andthe like. Examples of other suitable bulk materials include BalafilconA, Hilafilcon A, Alphafilcon A, Bilafilcon B, samfilcon A and the like.

In another embodiment, a biomedical device to be surface modifiedincludes a device which is formed from materials which are amphiphilicsegmented copolymers containing at least one hydrophobic segment and atleast one hydrophilic segment which are linked through a bond or abridge member.

It is particularly useful to employ biocompatible materials hereinincluding both soft and rigid materials commonly used for ophthalmiclenses, including contact lenses. In general, non-hydrogel materials arehydrophobic polymeric materials that do not contain water in theirequilibrium state. Typical non-hydrogel materials comprise siliconeacrylics, such as those formed of bulky silicone monomers (e.g.,tris(trimethylsiloxy)silylpropyl methacrylate, commonly known as “TRIS”monomer), methacrylate end-capped poly(dimethylsiloxane) prepolymer, orsilicones having fluoroalkyl side groups (polysiloxanes are alsocommonly known as silicone polymers).

On the other hand, hydrogel materials comprise hydrated, crosslinkedpolymeric systems containing water in an equilibrium state. Hydrogelmaterials contain about 5 wt. % water or more (up to, for example, about80 wt. %). The preferred hydrogel materials, include silicone hydrogelmaterials. In one preferred embodiment, materials include vinylfunctionalized polydimethylsiloxanes copolymerized with hydrophilicmonomers as well as fluorinated methacrylates and methacrylatefunctionalized fluorinated polyethylene oxides copolymerized withhydrophilic monomers. Representative examples of suitable materials foruse herein include those disclosed in U.S. Pat. Nos. 5,310,779;5,387,662; 5,449,729; 5,512,205; 5,610,252; 5,616,757; 5,708,094;5,710,302; 5,714,557 and 5,908,906, the contents of which areincorporated by reference herein.

In one embodiment, hydrogel materials for biomedical devices, such ascontact lenses, can contain a hydrophilic monomer such as one or moreunsaturated carboxylic acids, vinyl lactams, amides, polymerizableamines, vinyl carbonates, vinyl carbamates, oxazolone monomers,copolymers thereof and the like and mixtures thereof. Useful amidesinclude acrylamides such as N,N-dimethylacrylamide andN,N-dimethylmethacrylamide. Useful vinyl lactams include cyclic lactamssuch as N-vinyl-2-pyrrolidone. Examples of other hydrophilic monomersinclude hydrophilic prepolymers such as poly(alkene glycols)functionalized with polymerizable groups. Examples of usefulfunctionalized poly(alkene glycols) include poly(diethylene glycols) ofvarying chain length containing monomethacrylate or dimethacrylate endcaps. In a preferred embodiment, the poly(alkene glycol) polymercontains at least two alkene glycol monomeric units. Still furtherexamples are the hydrophilic vinyl carbonate or vinyl carbamate monomersdisclosed in U.S. Pat. No. 5,070,215, and the hydrophilic oxazolonemonomers disclosed in U.S. Pat. No. 4,910,277. Other suitablehydrophilic monomers will be apparent to one skilled in the art. Inanother embodiment, a hydrogel material can contain asiloxane-containing monomer and at least one of the aforementionedhydrophilic monomers and/or prepolymers.

Non-limited examples of hydrophobic monomers are C₁-C₂₀ alkyl and C₃-C₂₀cycloalkyl (meth)acrylates, substituted and unsubstituted aryl(meth)acrylates (wherein the aryl group comprises 6 to 36 carbon atoms),(meth) acrylonitrile, styrene, lower alkyl styrene, lower alky vinylethers, and C₂-C₁₀ perfluoroalkyl (meth)acrylates and correspondinglypartially fluorinate (meth)acrylates.

A wide variety of materials can be used herein, and silicone hydrogelcontact lens materials are particularly preferred. Silicone hydrogelsgenerally have a water content greater than about 5 wt. % and morecommonly between about 10 to about 80 wt. %. Such materials are usuallyprepared by polymerizing a mixture containing at least onesilicone-containing monomer and at least one hydrophilic monomer.Typically, either the silicone-containing monomer or the hydrophilicmonomer functions as a crosslinking agent (a crosslinker being definedas a monomer having multiple polymerizable functionalities) or aseparate crosslinker may be employed. Applicable silicone-containingmonomers for use in the formation of silicone hydrogels are well knownin the art and numerous examples are provided in U.S. Pat. Nos.4,136,250; 4,153,641; 4,740,533; 5,034,461; 5,070,215; 5,260,000;5,310,779; and 5,358,995.

Representative examples of applicable silicon-containing monomersinclude bulky polysiloxanylalkyl(meth)acrylic monomers. An example of abulky polysiloxanylalkyl(meth)acrylic monomer is represented by thestructure of Formula I:

wherein X denotes —O— or —NR— wherein R denotes hydrogen or a C₁-C₄alkyl; each R¹ independently denotes hydrogen or methyl; each R²independently denotes a lower alkyl radical, phenyl radical or a grouprepresented by

wherein each R^(2′) independently denotes a lower alkyl or phenylradical; and h is 1 to 10.

Representative examples of other applicable silicon-containing monomersinclude, but are not limited to, bulky polysiloxanylalkyl carbamatemonomers as generally depicted in Formula Ia:

wherein X denotes —NR—; wherein R denotes hydrogen or a C₁-C₄ alkyl; R¹denotes hydrogen or methyl; each R² independently denotes a lower alkylradical, phenyl radical or a group represented by

wherein each R^(2′) independently denotes a lower alkyl or phenylradical; and h is 1 to 10, and the like.

Examples of bulky monomers are3-methacryloyloxypropyltris(trimethyl-siloxy)silane ortris(trimethylsiloxy)silylpropyl methacrylate, sometimes referred to asTRIS and tris(trimethylsiloxy)silylpropyl vinyl carbamate, sometimesreferred to as TRIS-VC and the like and mixtures thereof.

Such bulky monomers may be copolymerized with a silicone macromonomer,which is a poly(organosiloxane) capped with an unsaturated group at twoor more ends of the molecule. U.S. Pat. No. 4,153,641 discloses, forexample, various unsaturated groups such as acryloxy or methacryloxygroups.

Another class of representative silicone-containing monomers includes,but is not limited to, silicone-containing vinyl carbonate or vinylcarbamate monomers such as, for example,1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;3-(trimethylsilyl)propyl vinyl carbonate;3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane];3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate;t-butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl vinylcarbonate; trimethylsilylmethyl vinyl carbonate and the like andmixtures thereof.

Another class of silicon-containing monomers includespolyurethane-polysiloxane macromonomers (also sometimes referred to asprepolymers), which may have hard-soft-hard blocks like traditionalurethane elastomers. They may be end-capped with a hydrophilic monomersuch as HEMA. Examples of such silicone urethanes are disclosed in avariety or publications, including Lai, Yu-Chin, “The Role of BulkyPolysiloxanylalkyl Methacrylates in Polyurethane-PolysiloxaneHydrogels,” Journal of Applied Polymer Science, Vol. 60, 1193-1199(1996). PCT Published Application No. WO 96/31792 discloses examples ofsuch monomers, which disclosure is hereby incorporated by reference inits entirety. Further examples of silicone urethane monomers arerepresented by Formulae II and III:

E(*D*A*D*G)_(a)*D*A*D*E′; or  (II)

E(*D*G*D*A)_(a)*D*A*D*E′; or  (III)

wherein:

-   -   D independently denotes an alkyl diradical, an alkyl cycloalkyl        diradical, a cycloalkyl diradical, an aryl diradical or an        alkylaryl diradical having 6 to about 30 carbon atoms;    -   G independently denotes an alkyl diradical, a cycloalkyl        diradical, an alkyl cycloalkyl diradical, an aryl diradical or        an alkylaryl diradical having 1 to about 40 carbon atoms and        which may contain ether, thio or amine linkages in the main        chain;    -   * denotes a urethane or ureido linkage;    -   a is at least 1;    -   A independently denotes a divalent polymeric radical of Formula        IV:

wherein each R^(s) independently denotes an alkyl or fluoro-substitutedalkyl group having 1 to about 10 carbon atoms which may contain etherlinkages between the carbon atoms; m′ is at least 1; and p is a numberthat provides a moiety weight of about 400 to about 10,000;

-   -   each of E and E′ independently denotes a polymerizable        unsaturated organic radical represented by Formula V:

wherein: R³ is hydrogen or methyl;

-   -   R⁴ is hydrogen, an alkyl radical having 1 to 6 carbon atoms, or        a —CO—Y—R⁶ radical wherein Y is —O—, —S— or —NH—;    -   R⁵ is a divalent alkylene radical having 1 to about 10 carbon        atoms;    -   R⁶ is a alkyl radical having 1 to about 12 carbon atoms;    -   X denotes —CO— or —OCO—;    -   Z denotes —O— or —NH—;    -   Ar denotes an aromatic radical having about 6 to about 30 carbon        atoms;    -   w is 0 to 6; x is 0 or 1; y is 0 or 1; and z is 0 or 1.

A preferred silicone-containing urethane monomer is represented byFormula VI:

wherein m is at least 1 and is preferably 3 or 4, a is at least 1 andpreferably is 1, p is a number which provides a moiety weight of about400 to about 10,000 and is preferably at least about 30, R⁷ is adiradical of a diisocyanate after removal of the isocyanate group, suchas the diradical of isophorone diisocyanate, and each E″ is a grouprepresented by:

In another embodiment of the present invention, a silicone hydrogelmaterial comprises (in bulk, that is, in the monomer mixture that iscopolymerized) about 5 to about 50 percent, and preferably about 10 toabout 25, by weight of one or more silicone macromonomers, about 5 toabout 75 percent, and preferably about 30 to about 60 percent, by weightof one or more polysiloxanylalkyl (meth)acrylic monomers, and about 10to about 50 percent, and preferably about 20 to about 40 percent, byweight of a hydrophilic monomer. In general, the silicone macromonomeris a poly(organosiloxane) capped with an unsaturated group at two ormore ends of the molecule. In addition to the end groups in the abovestructural formulas, U.S. Pat. No. 4,153,641 discloses additionalunsaturated groups, including acryloxy or methacryloxy.Fumarate-containing materials such as those disclosed in U.S. Pat. Nos.5,310,779; 5,449,729 and 5,512,205 are also useful substrates inaccordance with the invention. The silane macromonomer may be asilicon-containing vinyl carbonate or vinyl carbamate or apolyurethane-polysiloxane having one or more hard-soft-hard blocks andend-capped with a hydrophilic monomer.

Another class of representative silicone-containing monomers includesfluorinated monomers. Such monomers have been used in the formation offluorosilicone hydrogels to reduce the accumulation of deposits oncontact lenses made therefrom, as disclosed in, for example, U.S. Pat.Nos. 4,954,587; 5,010,141; 5,079,319 and 7,994,356. Also, the use ofsilicone-containing monomers having certain fluorinated side groups,i.e., —(CF₂)—H, have been found to improve compatibility between thehydrophilic and silicone-containing monomeric units. See, e.g., U.S.Pat. Nos. 5,321,108 and 5,387,662.

The above silicone materials are merely exemplary, and other materialsfor use as substrates that can benefit by being coated with thehydrophilic coating composition according to the present invention andhave been disclosed in various publications and are being continuouslydeveloped for use in contact lenses and other medical devices can alsobe used. For example, a biomedical device can be formed from at least acationic monomer such as cationic silicone-containing monomer orcationic fluorinated silicone-containing monomers.

Contact lenses for application of the present invention can bemanufactured employing various conventional techniques, to yield ashaped article having the desired posterior and anterior lens surfaces.Spincasting methods are disclosed in U.S. Pat. Nos. 3,408,429 and3,660,545; and static casting methods are disclosed in U.S. Pat. Nos.4,113,224, 4,197,266 and 5,271,876. Curing of the monomeric mixture maybe followed by a machining operation in order to provide a contact lenshaving a desired final configuration. As an example, U.S. Pat. No.4,555,732 discloses a process in which an excess of a monomeric mixtureis cured by spincasting in a mold to form a shaped article having ananterior lens surface and a relatively large thickness. The posteriorsurface of the cured spincast article is subsequently lathe cut toprovide a contact lens having the desired thickness and posterior lenssurface. Further machining operations may follow the lathe cutting ofthe lens surface, for example, edge-finishing operations.

Typically, an organic diluent is included in the initial monomericmixture in order to minimize phase separation of polymerized productsproduced by polymerization of the monomeric mixture and to lower theglass transition temperature of the reacting polymeric mixture, whichallows for a more efficient curing process and ultimately results in amore uniformly polymerized product. Sufficient uniformity of the initialmonomeric mixture and the polymerized product is of particularimportance for silicone hydrogels, primarily due to the inclusion ofsilicone-containing monomers which may tend to separate from thehydrophilic comonomer.

Suitable organic diluents include, for example, monohydric alcohols suchas C₆-C₁₀ straight-chained aliphatic monohydric alcohols, e.g.,n-hexanol and n-nonanol; diols such as ethylene glycol; polyols such asglycerin; ethers such as diethylene glycol monoethyl ether; ketones suchas methyl ethyl ketone; esters such as methyl enanthate; andhydrocarbons such as toluene. Preferably, the organic diluent issufficiently volatile to facilitate its removal from a cured article byevaporation at or near ambient pressure.

Generally, the diluent may be included at about 5 to about 60 percent byweight of the monomeric mixture, with about 10 to about 50 percent byweight being especially preferred. If necessary, the cured lens may besubjected to solvent removal, which can be accomplished by evaporationat or near ambient pressure or under vacuum. An elevated temperature canbe employed to shorten the time necessary to evaporate the diluent.

Following removal of the organic diluent, the lens can then be subjectedto mold release and optional machining operations. The machining stepincludes, for example, buffing or polishing a lens edge and/or surface.Generally, such machining processes may be performed before or after thearticle is released from a mold part. As an example, the lens may be dryreleased from the mold by employing vacuum tweezers to lift the lensfrom the mold.

As one skilled in the art will readily appreciate, biomedical devicesurface functional groups of the biomedical device disclosed herein maybe inherently present at the surface of the device. However, if thebiomedical device contains too few or no functional groups, the surfaceof the device can be modified by known techniques, for example, plasmachemical methods (see, for example, WO 94/06485), or conventionalfunctionalization with groups such as —OH, or —CO₂H. Suitable biomedicaldevice surface functional groups of the biomedical device include a widevariety of groups well known to the skilled artisan. Representativeexamples of such functional groups include, but are not limited to,hydroxy groups, cis 1,2-diols, cis 1,3-diols, α hydroxy acid groups(e.g., sialic acid, salicylic acid), carboxylic acids, di-carboxylicacids, catechols, silanols, silicates and the like.

In one embodiment, the foregoing biomedical devices are subjected to anoxidative surface treatment such as corona discharge or plasma oxidationfollowed by treatment with the one or more grafted glycosaminoglycanpolymers and/or one or more crosslinked polymeric network disclosedherein. For example, a biomedical device such as a silicone hydrogelformulation containing hydrophilic polymers, such aspoly(N,N-dimethylacrylamide) or poly(N-vinylpyrrolidinone), is subjectedto an oxidative surface treatment to form at least silicates on thesurface of the lens and then the lens is treated with an aqueoussolution containing the one or more grafted glycosaminoglycan polymersand/or one or more crosslinked polymeric networks disclosed herein torender a lubricious, stable, highly wettable surface coating. Thecomplexation treatment is advantageously performed under autoclaveconditions (sterilization conditions).

The standard process such as a plasma process (also referred to as“electrical glow discharge processes”) provides a thin, durable surfaceupon the biomedical device prior to binding the one or more graftedglycosaminoglycan polymers and/or one or more crosslinked polymericnetworks to at least a portion of the surface thereof. Examples of suchplasma processes are provided in U.S. Pat. Nos. 4,143,949; 4,312,575;and 5,464,667.

Although plasma processes are generally well known in the art, a briefoverview is provided below. Plasma surface treatments involve passing anelectrical discharge through a gas at low pressure. The electricaldischarge may be at radio frequency (typically 13.56 MHz), althoughmicrowave and other frequencies can be used. Electrical dischargesproduce ultraviolet (UV) radiation, in addition to being absorbed byatoms and molecules in their gas state, resulting in energetic electronsand ions, atoms (ground and excited states), molecules, and radicals.Thus, a plasma is a complex mixture of atoms and molecules in bothground and excited states, which reach a steady state after thedischarge is begun. The circulating electrical field causes theseexcited atoms and molecules to collide with one another as well as thewalls of the chamber and the surface of the material being treated.

The deposition of a coating from a plasma onto the surface of a materialhas been shown to be possible from high-energy plasmas without theassistance of sputtering (sputter-assisted deposition). Monomers can bedeposited from the gas phase and polymerized in a low pressureatmosphere (about 0.005 to about 5 torr, and preferably about 0.001 toabout 1 torr) onto a substrate utilizing continuous or pulsed plasmas,suitably as high as about 1000 watts. A modulated plasma, for example,may be applied about 100 milliseconds on then off. In addition, liquidnitrogen cooling has been utilized to condense vapors out of the gasphase onto a substrate and subsequently use the plasma to chemicallyreact these materials with the substrate. However, plasmas do notrequire the use of external cooling or heating to cause the deposition.Low or high wattage (e.g., about 5 to about 1000, and preferably about20 to about 500 watts) plasmas can coat even the most chemical-resistantsubstrates, including silicones.

After initiation by a low energy discharge, collisions between energeticfree electrons present in the plasma cause the formation of ions,excited molecules, and free-radicals. Such species, once formed, canreact with themselves in the gas phase as well as with furtherground-state molecules. The plasma treatment may be understood as anenergy dependent process involving energetic gas molecules. For chemicalreactions to take place at the surface of the lens, one needs therequired species (element or molecule) in terms of charge state andparticle energy. Radio frequency plasmas generally produce adistribution of energetic species. Typically, the “particle energy”refers to the average of the so-called Boltzman-style distribution ofenergy for the energetic species. In a low-density plasma, the electronenergy distribution can be related by the ratio of the electric fieldstrength sustaining the plasma to the discharge pressure (E/p). Theplasma power density P is a function of the wattage, pressure, flowrates of gases, etc., as will be appreciated by the skilled artisan.Background information on plasma technology, hereby incorporated byreference, includes the following: A. T. Bell, Proc. Intl. Conf Phenom.Ioniz. Gases, “Chemical Reaction in Nonequilibrium Plasmas”, 19-33(1977); J. M. Tibbitt, R. Jensen, A. T. Bell, M. Shen, Macromolecules,“A Model for the Kinetics of Plasma Polymerization”, 3, 648-653 (1977);J. M. Tibbitt, M. Shen, A. T. Bell, J. Macromol. Sci.-Chem., “StructuralCharacterization of Plasma-Polymerized Hydrocarbons”, A10, 1623-1648(1976); C. P. Ho, H. Yasuda, J. Biomed, Mater. Res., “Ultrathin coatingof plasma polymer of methane applied on the surface of silicone contactlenses”, 22, 919-937 (1988); H. Kobayashi, A. T. Bell, M. Shen,Macromolecules, “Plasma Polymerization of Saturated and UnsaturatedHydrocarbons”, 3, 277-283 (1974); R. Y. Chen, U.S. Pat. No. 4,143,949,Mar. 13, 1979, “Process for Putting a Hydrophilic Coating on aHydrophobic Contact lens”; and H. Yasuda, H. C. Marsh, M. O. Bumgarner,N. Morosoff, J. of Appl. Poly. Sci., “Polymerization of OrganicCompounds in an Electroless Glow Discharge. VI Acetylene with UnusualCo-monomers”, 19, 2845-2858 (1975).

Based on this previous work in the field of plasma technology, theeffects of changing pressure and discharge power on the rate of plasmamodification can be understood. The rate generally decreases as thepressure is increased. Thus, as pressure increases the value of E/p, theratio of the electric field strength sustaining the plasma to the gaspressure decreases and causes a decrease in the average electron energy.The decrease in electron energy in turn causes a reduction in the ratecoefficient of all electron-molecule collision processes. A furtherconsequence of an increase in pressure is a decrease in electrondensity. Providing that the pressure is held constant, there should be alinear relationship between electron density and power.

In practice, contact lenses are surface-treated by placing them, intheir unhydrated state, within an electric glow discharge reactionvessel (e.g., a vacuum chamber). Such reaction vessels are commerciallyavailable. The lenses may be supported within the vessel on an aluminumtray (which acts as an electrode) or with other support devices designedto adjust the position of the lenses. The use of a specialized supportdevices which permit the surface treatment of both sides of a lens areknown in the art and may be used herein.

As mentioned above, the surface of the lens, for example, a siliconehydrogel continuous-wear lens is initially treated, e.g., oxidized, bythe use of a plasma to render the subsequent grafted glycosaminoglycanpolymer and/or crosslinked polymeric network surface deposition moreadherent to the lens. Such a plasma treatment of the lens may beaccomplished in an atmosphere composed of a suitable media, e.g., anoxidizing media such as oxygen, air, water, peroxide, O₂ (oxygen gas),etc., or appropriate combinations thereof, typically at an electricdischarge frequency of about 13.56 Mhz, preferably between about 20 toabout 500 watts at a pressure of about 0.1 to about 1.0 torr, preferablyfor about 10 seconds to about 10 minutes or more, more preferably about1 to about 10 minutes. It is preferred that a relatively “strong” plasmais utilized in this step, for example, ambient air drawn through a fivepercent (5%) hydrogen peroxide solution. Those skilled in the art willknow other methods of improving or promoting adhesion for bonding of thesubsequent grafted glycosaminoglycan polymer and/or crosslinkedpolymeric network layer.

The biomedical device is then subjected to a surface treatment. Ingeneral, the biomedical device such as a wettable silicone-basedhydrogel lens is contacted with a solution containing at least one ormore of the grafted glycosaminoglycan polymers and/or one or more of thecrosslinked polymeric networks disclosed herein, whereby the graftedglycosaminoglycan polymer and/or crosslinked polymeric network forms acomplex with the plurality of biomedical device surface functionalgroups on the surface of the biomedical device. The biomedical devicescan either be contacted with the solution containing at least one ormore of the grafted glycosaminoglycan polymers and/or one or more of thecrosslinked polymeric networks directly in the mold assembly or thebiomedical device can be released from the mold assembly and thencontacted with the solution. The solutions can be water-based solutionscontaining one or more of the grafted glycosaminoglycan polymers and/orone or more of the crosslinked polymeric networks and render alubricious, stable, highly wettable surface. The complexation treatmentis advantageously performed under autoclave conditions.

The solutions generally include compositions for direct instillation inthe eye, including eye drop solutions and contact lens treatingsolutions distilled directly in the eye such as for rewetting a contactlens while worn as well as those that also qualify as a multi-purposesolution. Ophthalmic compositions also include compositions instilledindirectly in the eye, such as contact lens treating solutions fortreating the contact lens prior to the lens being inserted on the eye ora packaging solution for storing the lens.

In an illustrative embodiment, the aqueous ophthalmic composition has anosmolality in a range from about 200 mOsmol/kg to about 500 mOsmol/kg,and is in the form of an eye care or a contact lens care productselected from the group consisting of eye drops, contact lenspreservative solution, contact lens cleaning solution, and contact lensmulti-purpose solution.

The ophthalmically acceptable solutions disclosed herein arephysiologically compatible. Specifically, the compositions must be“ophthalmically safe” for use with a contact lens, meaning that acontact lens treated with the solution is generally suitable and safefor direct placement on the eye without rinsing, that is, the solutionis safe and comfortable for daily contact with the eye via a contactlens that has been wetted with the solution. An ophthalmically safecomposition has a tonicity and pH that is compatible with the eye andcomprises materials, and amounts thereof, that are non-cytotoxicaccording to ISO (International Standards Organization) standards andU.S. FDA regulations. The compositions should be sterile in that theabsence of microbial contaminants in the product prior to release mustbe statistically demonstrated to the degree necessary for such products.

In general, one or more of the grafted glycosaminoglycan polymers and/orone or more of the crosslinked polymeric networks disclosed herein canbe present in the ophthalmic solution in an amount ranging from about0.001 to about 10% w/w. In another embodiment, one or more of thegrafted glycosaminoglycan polymers and/or one or more of the crosslinkedpolymeric networks disclosed herein can be present in the ophthalmicsolution in an amount ranging from about 0.1 to about 2% w/w.

The ophthalmic solutions may be in the form of drops and are useful as acomponent of a contact lens cleaning, disinfecting or conditioningcomposition containing such materials. In one embodiment, thecompositions and/or solutions disclosed herein may be formulated as a“multi-purpose solution”. A multi-purpose solution is useful forcleaning, disinfecting, storing, and rinsing a lens, particularly softcontact lenses. Multi-purpose solutions do not exclude the possibilitythat some wearers, for example, wearers particularly sensitive tochemical disinfectants or other chemical agents, may prefer to rinse orwet a contact lens with another solution, for example, a sterile salinesolution prior to insertion of the lens. The term “multi-purposesolution” also does not exclude the possibility of periodic cleaners notused on a daily basis or supplemental cleaners for further removingproteins, for example, enzyme cleaners, which are typically used on aweekly basis. By the term “cleaning” is meant that the solution containsone or more agents in sufficient concentrations to loosen and removeloosely held lens deposits and other contaminants on the surface of acontact lens, which may be used in conjunction with digital manipulation(e.g., manual rubbing of the lens with a solution) or with an accessorydevice that agitates the solution in contact with the lens, for example,a mechanical cleaning aid.

Traditionally, multi-purpose solutions on the market have required aregimen involving mechanical rubbing of the lens with the multi-purposesolution, in order to provide the required disinfection and cleaning.Such a regimen is required under governmental regulatory authorities(e.g., the FDA or U.S. Food & Drug Administration (FDA)) for a ChemicalDisinfection System that does not qualify as a Chemical DisinfectingSolution. In one embodiment of the present invention, it is possible toformulate a cleaning and disinfecting product that, on one hand, is ableto provide improved cleaning and disinfection in the absence of arubbing regimen and, on the other hand, is gentle enough to be used as awetting agent, e.g. as an eye drop. For example, a product qualifying asa Chemical Disinfecting Solution must meet biocidal performance criteriaestablished by the US FDA for Contact Lens Care Products (May 1, 1997)which criteria does not involve rubbing of the lenses. In one embodimentof the present invention, a composition is formulated to meet therequirements of the FDA or ISO Stand-Alone Procedure for contact lensdisinfecting products. Similarly, the compositions disclosed herein canbe formulated to provide enhanced cleaning without the use of a rubbingregimen. Such formulations may ensure higher patient compliance andgreater universal appeal than traditional multi-purpose disinfecting andcleaning products. A multi-purpose solution can have a viscosity of lessthan about 75 cps, or from about 1 to about 50 cps, or from about 1 toabout 25 cps or at least about 95 percent weight by volume water in thetotal composition.

The aqueous ophthalmic solutions may contain, in addition to one or moreof the grafted glycosaminoglycan polymers and/or one or more of thecrosslinked polymeric networks disclosed herein, one or moreantimicrobial agents, preservatives and the like. The compositionsgenerally include a primary antimicrobial agent. Antimicrobial agentssuitable for use herein include chemicals that derive theirantimicrobial activity through a chemical or physiochemical interactionwith the microbial organisms. These agents may be used alone or incombination.

Suitable known ophthalmically acceptable antimicrobial agents include,but are not limited to, a biguanide or a salt or free base thereof,quaternary ammonium compound or a salt thereof or free base thereof;terpene or derivative thereof, a branched, glycerol monoalkyl ether, abranched, glycerol monoalkyl amine, a branched, glycerol monoalkylsulphide, a fatty acid monoester, wherein the fatty acid monoestercomprises an aliphatic fatty acid portion having six to fourteen carbonatoms, and an aliphatic hydroxyl portion, amidoamine compound, and thelike and combinations thereof.

Suitable biguanide antimicrobial agents for use in the ophthalmiccompositions can be any biguanide or salt thereof known in the art.Representative biguanides include non-polymeric biguanides, polymericbiguanides, salts thereof, free bases thereof and the like and mixturesthereof. Representative non-polymeric biguanides are thebis(biguanides), such as alexidine, chlorhexidine, salts of alexidine,e.g., alexidine HCl, salts of chlorhexidine, alexidine free base, andthe like and mixtures thereof. The salts of alexidine and chlorhexidinecan be either organic or inorganic and are typically disinfectingnitrates, acetates, phosphates, sulfates, halides and the like.

Representative polymeric biguanides include polymeric hexamethylenebiguanides (PHMB) (commercially available from Zeneca, Wilmington,Del.), their polymers and water-soluble salts. In one embodiment,water-soluble polymeric biguanides for use herein can have a numberaverage molecular weight of at least about 1,000 or a number averagemolecular weight from about 1,000 to about 50,000. Suitablewater-soluble salts of the free bases include, but are not limited to,hydrochloride, borate, acetate, gluconate, sulfonate, tartrate andcitrate salts. Generally, the hexamethylene biguanide polymers, alsoreferred to as polyaminopropyl biguanide (PAPB), have number averagemolecular weights of up to about 100,000. Such compounds are known andare disclosed in U.S. Pat. No. 4,758,595 which is incorporated herein byreference.

PHMB or polyhexamethylenbiguanide is best described as a polymericbiguanide composition comprising at least three and preferably at leastsix biguanide polymers, which we refer to as PHMB-A, PHMB-CG andPHMB-CGA, the general chemical structures of which are depicted below.

For each of these polymers, “n” represents the average number ofrepeating groups. Actually, a distribution of polymer length would existfor each of the polymers shown. The prior synthetic routes to PHMBprovided a polymeric biguanide composition with about 50% by weight ofthe polymeric composition as PHMB-CGA, that is, having a cyanoguanidinoend cap on one end and an amine on the other end, about 25% by weightPHMB-A and about 25% by weight PHMB-CG. Given this approximate weightratio of the three major PHMB polymers above, the percentage ofcyanoguardino end caps is also about 50% of the total number of terminalgroups. In this application we refer to this conventional polymericbiguanide composition as poly(hexamethylene biguanide) or PHMB.

A polymeric biguanide composition comprising less than 18 mole % ofterminal amine groups as measured by ¹³C NMR can also be used. Thepolymeric biguanide composition can also be characterized by a relativeincrease in the molar concentration of terminal guanidine groups orterminal cyanoguardino groups. For example, in one embodiment, thebiguanide composition comprises less than about 18 mole % of terminalamine groups and about 40 mol % or greater of terminal guanidine groups.In another embodiment, the biguanide composition comprises less thanabout 18 mole % of terminal amine groups and about 55 mol % or greaterof terminal guanidine groups.

In this application, we refer to this biguanide composition as PHMB-CG*.We also refer to polymeric biguanide compositions in the generic senseas “hexamethylene biguanides”, which one of ordinary skill in the artwould recognize to include both PHMB as well as PHMB-CG*.

Representative examples of suitable quaternary ammonium compounds foruse in the ophthalmic compositions of the present invention include, butare not limited to, poly[(dimethyliminio)-2-butene-1,4-diyl chloride]and[4-tris(2-hydroxyethyl)ammonio]-2-butenyl-w-[tris(2-hydroxyethyl)ammonio]-dichloride(chemical registry no. 75345-27-6) generally available as Polyquaternium1 under the tradename ONAMER® M (Stepan Company, Northfield, Ill), andthe like and mixtures thereof.

Suitable terpene antimicrobial agents for use in the ophthalmiccompositions of the present invention include any monoterpene,sesquiterpene and/or diterpene or derivatives thereof. Acyclic,monocyclic and/or bicyclic mono-, sesqui- and/or diterpenes, and thosewith higher numbers of rings, can be used. A “derivative” of a terpeneas used herein shall be understood to mean a terpene hydrocarbon havingone or more functional groups such as terpene alcohols, terpene ethers,terpene esters, terpene aldehydes, terpene ketones and the like andcombinations thereof. Here, both the trans and also the cis isomers aresuitable. The terpenes as well as the terpene moiety in the derivativecan contain from 6 to about 100 carbon atoms and preferably from about10 to about 25 carbon atoms.

Representative examples of suitable terpene alcohol antimicrobial agentsinclude verbenol, transpinocarveol, cis-2-pinanol, nopol, isoborneol,carbeol, piperitol, thymol, α-terpineol, terpinen-4-ol, menthol,1,8-terpin, dihydro-terpineol, nerol, geraniol, linalool, citronellol,hydroxycitronellol, 3,7-dimethyl octanol, dihydro-myrcenol,tetrahydro-alloocimenol, perillalcohol, falcarindiol and the like andmixtures thereof.

Representative examples of suitable terpene ether and terpene esterantimicrobial agents include 1,8-cineole, 1,4-cineole, isobornylmethylether, rose pyran, α-terpinyl methyl ether, menthofuran,trans-anethole, methyl chavicol, allocimene diepoxide, limonenemono-epoxide, isobornyl acetate, nonyl acetate, α-terpinyl acetate,linalyl acetate, geranyl acetate, citronellyl acetate, dihydro-terpinylacetate, meryl acetate and the like and mixtures thereof.

Representative examples of terpene aldehyde and terpene ketoneantimicrobial agents include myrtenal, campholenic aldehyde,perillaldehyde, citronellal, citral, hydroxy citronellal, camphor,verbenone, carvenone, dihydro-carvone, carvone, piperitone, menthone,geranyl acetone, pseudo-ionone, α-ionine, iso-pseudo-methyl ionone,n-pseudo-methyl ionone, iso-methyl ionone, n-methyl ionone and the likeamd mixtures thereof. Any other terpene hydrocarbons having functionalgroups known in the art may be used herein in the inventive composition.

In one embodiment, suitable terpenes or derivatives thereof asantimicrobial agents include, but are not limited to, tricyclene,α-pinene, terpinolene, carveol, amyl alcohol, nerol, β-santalol, citral,pinene, nerol, b-ionone, caryophillen (from cloves), guaiol,anisaldehyde, cedrol, linalool, d-limonene (orange oil, lemon oil),longifolene, anisyl alcohol, patchouli alcohol, α-cadinene, 1,8-cineole,ρ-cymene, 3-carene, ρ-8-mentane, trans-menthone, borneol, α-fenchol,isoamyl acetate, terpin, cinnamic aldehyde, ionone, geraniol (from rosesand other flowers), myrcene (from bayberry wax, oil of bay and verbena),nerol, citronellol, carvacrol, eugenol, carvone, α-terpineol, anethole,camphor, menthol, limonene, nerolidol, farnesol, phytol, carotene(vitamin A₁), squalene, thymol, tocotrienol, perillyl alcohol, borneol,simene, carene, terpenene, linalool, 1-terpene-4-ol, zingiberene (fromginger) and the like and mixtures thereof.

In one embodiment, the compound of component (ii) of the ophthalmiccomposition comprises a branched, glycerol monoalkyl ether. In anotherembodiment, the compound of component (ii) of the ophthalmic compositioncomprises a branched, glycerol monoalkyl amine. In another embodiment,the compound of component (ii) of the ophthalmic composition comprises abranched, glycerol monoalkyl sulphide. In still another embodiment, thecompound of component (ii) of the ophthalmic composition comprises anyone mixture of a branched, glycerol monoalkyl ether, a branched,glycerol monoalkyl amine or a branched, glycerol monoalkyl sulphide.

In one embodiment, the branched, glycerol monoalkyl ether for use in theophthalmic compositions of the present invention is3-[(2-ethylhexyl)oxy]-1,2-propanediol (EHOPD). In another embodiment,the branched, glycerol monoalkyl amine is3-[(2-ethylhexyl)amino]-1,2-propanediol (EHAPD). In another embodiment,the branched, glycerol monoalkyl sulphide is3-[(2-ethylhexyl)thio]-1,2-propanediol (EHSPD). In still anotherembodiment, the ophthalmic composition comprises any one mixture ofEHOPD, EHAPD and EHSPD. The chemical structures of EHOPD, EHAPD andEHSPD are provided below.

EHOPD is also referred to as octoxyglycerin and is sold under thetradename Sensiva® SC50 (Schülke & Mayr). EHOPD is a branched, glycerolmonoalkyl ether known to be gentle to the skin, and to exhibitantimicrobial activity against a variety of Gram-positive bacteria suchas Micrococcus luteus, Corynebacterium aquaticum, Corynebacteriumflavescens, Corynebacterium callunae, and Corynebacterium nephredi.Accordingly, EHOPD is used in various skin deodorant preparations atconcentrations between about 0.2 and 3 percent by weight. EHAPD can beprepared from 2-ethylhexylamine and 2,3-epoxy-1-propanediol usingchemistry well known to those of ordinary skill in the art. EHSPD can beprepared from 2-ethylhexylthiol and 2,3-epoxy-1-propanediol usingchemistry well known to those of ordinary skill in the art.

Suitable fatty acid monoesters for use in the ophthalmic compositionsdisclosed herein include those fatty acid monoesters comprising analiphatic fatty acid portion having six to fourteen carbon atoms, and analiphatic hydroxyl portion.

The term “aliphatic” refers to a straight or branched, saturated orunsaturated hydrocarbon having six to fourteen carbon atoms. In oneembodiment, the aliphatic fatty acid portion is a straight chain,saturated or unsaturated hydrocarbon with eight to ten carbons. Inanother embodiment, the aliphatic fatty acid portion is a branchedchain, saturated or unsaturated hydrocarbon with eight to ten carbons.

The aliphatic hydroxyl portion of the fatty acid monoester can be anyaliphatic compound with at least one hydroxyl group. In many of theembodiments, the aliphatic hydroxyl portion will have from three to ninecarbons. The aliphatic hydroxyl portion can include, but is not limitedto, propylene glycol, glycerol, a polyalkylene glycol, e.g.,polyethylene glycol or polypropylene glycol, a cyclic polyol, e.g.,sorbitan, glucose, mannose, sucrose, fructose, fucose and inisitol andderivatives thereof, and a linear polyol, e.g., mannitol and sorbitoland derivatives thereof and the like and mixtures thereof.

Representative examples of suitable amidoamines for use in theophthalmic compositions disclosed herein include those amidoamines ofthe general formula: R¹⁵—(OCH₂CH₂)_(m)—X—(CH₂)_(n)—Y wherein R¹⁵ is a isC₆-C₃₀ saturated or unsaturated hydrocarbon including by way of example,a straight or branched, substituted or unsubstituted alkyl, alkylaryl,or alkoxyaryl group; m is zero to 16; n is 2 to 16; X is —C(O)—NR¹⁶— or—R¹⁶N—C(O)—; Y is —N(R¹⁷)₂ wherein each of R¹⁶ and R¹⁷ independently arehydrogen, a C₁-C₈ saturated or unsaturated alkyl or hydroxyalkyl, or apharmaceutically acceptable salt thereof.

Some of the amidoamines utilized herein are available from commercialsources. For example, myristamidopropyl dimethylamine is available fromAlcon Inc. (Fort Worth, Tx.) under the tradename Aldox®; lauramidopropyldimethylamine is available from Inolex Chemical Company (Philadelphia,Pa.) under the tradename LEXAMINE® L-13; and stearamidopropyldimethylamine is also from Inolex Chemical Company as LEXAMINE® S-13.The above-described amidoamines can be synthesized in accordance withknown techniques, including those described in U.S. Pat. No. 5,573,726.

The amount of the primary antimicrobial agent may vary depending on thespecific agent employed. For the aforementioned organicnitrogen-containing agent, typically, such agents are present inconcentrations ranging from about 0.00001 to about 0.5 wt. %, or fromabout 0.00003 to about 0.05 wt. %. For sorbic acid, higher amounts maybe required, typically about 0.01 to about 1 wt. %, or from about 0.1 toabout 0.5 wt. %. It is preferred that the antimicrobial agent is used inan amount that will at least partially reduce the microorganismpopulation in the formulations employed. If desired, the antimicrobialagent may be employed in a disinfecting amount, which will reduce themicrobial bioburden by at least two log orders in four hours and morepreferably by one log order in one hour. Most preferably, a disinfectingamount is an amount which will eliminate the microbial burden on acontact lens when used in regimen for the recommended soaking time (FDAChemical Disinfection Efficacy Test-July, 1985 Contact Lens SolutionDraft Guidelines).

The aqueous solutions may further contain one or more other componentsthat are commonly present in ophthalmic solutions, for example,surfactants, tonicity adjusting agents; buffering agents; chelatingagents; pH adjusting agents, viscosity modifying agents, and demulcentsand the like as discussed hereinabove, and which aid in makingophthalmic compositions more comfortable to the user and/or moreeffective for their intended use.

The pH of the solutions and/or compositions disclosed herein may bemaintained within the range of pH of about 4.0 to about 9.0, or about5.0 to about 8.0, or about 6.0 to about 8.0, or about 6.5 to about 7.8.In one embodiment, pH values of greater than or equal to about 7 atmost.

In one embodiment, the biomedical device is transferred to an individuallens package containing a buffered saline solution containing at leastone or more of the grafted glycosaminoglycan polymers and/or one or moreof the crosslinked polymeric networks disclosed herein. Generally, apackaging system for the storage of an ophthalmic device disclosedherein includes at least a sealed container containing one or moreunused ophthalmic devices immersed in an aqueous packaging solution. Inone embodiment, the sealed container is a hermetically sealedblister-pack, in which a concave well containing an ophthalmic devicesuch as a contact lens is covered by a metal or plastic sheet adaptedfor peeling in order to open the blister-pack. The sealed container maybe any suitable generally inert packaging material providing areasonable degree of protection to the lens, preferably a plasticmaterial such as polyalkylene, PVC, polyamide, and the like.

The amount of the one or more grafted glycosaminoglycan polymers and/orone or more crosslinked polymeric networks employed in a packagingsolution for storing an ophthalmic device in a packaging systemdisclosed herein is an amount effective to improve the surfaceproperties of the ophthalmic device. It is believed the graftedglycosaminoglycan polymers and crosslinked polymeric networks enhanceinitial and extended comfort when a contact lens, packaged in thesolution and then removed from the packaging system, is placed on theeye for wearing. In one embodiment, the concentration of the one or moregrafted glycosaminoglycan polymers and/or one or more crosslinkedpolymeric networks in the packaging solution will range from about 0.01to about 20% w/w. In one embodiment, the concentration of the one ormore crosslinked polymeric networks present in the packaging solutionwill range from about 0.02 to about 0.1% w/w.

The packaging solutions disclosed herein are physiologically compatible.Specifically, the solution must be “ophthalmically safe” for use with alens such as a contact lens, meaning that a contact lens treated withthe solution is generally suitable and safe for direct placement on theeye without rinsing, that is, the solution is safe and comfortable fordaily contact with the eye via a contact lens that has been wetted withthe solution. An ophthalmically safe solution has a tonicity and pH thatis compatible with the eye and includes materials, and amounts thereof,that are non-cytotoxic according to ISO standards and U.S. Food & DrugAdministration (FDA) regulations.

The packaging solution should also be sterile in that the absence ofmicrobial contaminants in the product prior to release must bestatistically demonstrated to the degree necessary for such products.The liquid media useful in the present invention are selected to have nosubstantial detrimental effect on the lens being treated or cared forand to allow or even facilitate the present lens treatment ortreatments. In one embodiment, the liquid media is aqueous-based. Aparticularly useful aqueous liquid medium is that derived from saline,for example, a conventional saline solution or a conventional bufferedsaline solution.

The pH of the packaging solutions should be maintained within the rangeof about 6 to about 9, or from about 6.5 to about 7.8. Suitable buffersmay be added, such as boric acid, sodium borate, potassium citrate,citric acid, sodium bicarbonate, TRIS and various mixed phosphatebuffers (including combinations of Na₂HPO₄, NaH₂PO₄ and KH₂PO₄) andmixtures thereof. Generally, buffers will be used in amounts rangingfrom about 0.05 to about 2.5 percent by weight of the solution. In oneembodiment, buffers will be used in amounts ranging from about 0.1 toabout 1.5 percent by weight of the solution. In one embodiment, thepackaging solutions of this invention will contain a borate buffer,e.g., a borate buffer containing one or more of boric acid, sodiumborate, potassium tetraborate, potassium metaborate or mixtures thereof.

In one embodiment, the packaging solution can further contain one ormore comfort agents to increase the stability of the graftedglycosaminoglycan polymers and/or crosslinked polymeric networks, aswell as increase the shelf life of the packaging solution. Suitablecomfort agents include, for example, polyols, antioxidants and complexcarbohydrates. Suitable polyols include, but are not limited to,glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose,glycerol, and trehalose. Suitable antioxidants include, but are notlimited to, alpha-tocopherol and other water soluble vitamin E moieties,ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine,epicatechin, gallic acid, resveratrol, ellagic acid, pychogenol,lycopene, astaxanthene, coenzyme Q10, caffeic acid, hydroquinonemonomethyl ether and butylated hydroxytoluene. Suitable complexcarbohydrates include, but are not limited to, tremella polysaccharidesand carboxymethyl cellulose. In one embodiment, the packaging solutionwill contain the one or more comfort agents in an amount ranging fromabout 0 to about 5 percent by weight of the solution. In anotherembodiment, the packaging solution will contain the one or more comfortagents in an amount ranging from about 0.01 to about 2 percent by weightof the solution.

Typically, the packaging solutions are also adjusted with tonicityagents, to approximate the osmotic pressure of normal lacrimal fluidswhich is equivalent to a 0.9 percent solution of sodium chloride or 2.5percent of glycerol solution. The packaging solutions are madesubstantially isotonic with physiological saline used alone or incombination, otherwise if simply blended with sterile water and madehypotonic or made hypertonic the lenses will lose their desirableoptical parameters. Correspondingly, excess saline may result in theformation of a hypertonic solution which will cause stinging and eyeirritation.

Suitable tonicity adjusting agents include, for example, sodium andpotassium chloride, dextrose, glycerin, calcium and magnesium chlorideand the like and mixtures thereof. These tonicity adjusting agents aretypically used individually in amounts ranging from about 0.01 to about2.5% w/v. In one embodiment, the tonicity adjusting agents are used inamounts ranging from about 0.2 to about 1.5% w/v. The tonicity agentwill be employed in an amount to provide a final osmotic value of atleast about 200 mOsm/kg. In one embodiment, the tonicity adjustingagents are used in an amount to provide a final osmotic value of fromabout 200 to about 400 mOsm/kg. In one embodiment, the tonicityadjusting agents are used in an amount to provide a final osmotic valueof from about 250 to about 350 mOsm/kg. In one embodiment, the tonicityadjusting agents are used in an amount to provide a final osmotic valueof from about 280 to about 320 mOsm/kg.

If desired, one or more additional components can be included in thepackaging solution. Such additional component or components are chosento impart or provide at least one beneficial or desired property to thepackaging solution. In general, the additional components may beselected from components which are conventionally used in one or moreophthalmic device care compositions. Suitable additional componentsinclude, for example, cleaning agents, wetting agents, nutrient agents,sequestering agents, viscosity builders, contact lens conditioningagents, antioxidants, and the like and mixtures thereof. Theseadditional components may each be included in the packaging solutions inan amount effective to impart or provide the beneficial or desiredproperty to the packaging solutions. For example, such additionalcomponents may be included in the packaging solutions in amounts similarto the amounts of such components used in other, e.g., conventional,contact lens care products.

Suitable sequestering agents include, for example, disodium ethylenediamine tetraacetate, alkali metal hexametaphosphate, citric acid,sodium citrate and the like and mixtures thereof.

Suitable viscosity builders include, for example, hydroxyethylcellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinylalcohol and the like and mixtures thereof.

Suitable antioxidants include, for example, sodium metabisulfite, sodiumthiosulfate, N-acetylcysteine, butylated hydroxyanisole, butylatedhydroxytoluene and the like and mixtures thereof.

The method of packaging and storing a biomedical device such as acontact lens includes at least packaging a biomedical device immersed inthe aqueous packaging solution described above. The method may includeimmersing the biomedical device in an aqueous packaging solution priorto delivery to the customer/wearer, directly following manufacture ofthe contact lens. Alternately, the packaging and storing in thepackaging solution may occur at an intermediate point before delivery tothe ultimate customer (wearer) but following manufacture andtransportation of the lens in a dry state, wherein the dry lens ishydrated by immersing the lens in the packaging solution. Consequently,a package for delivery to a customer may include a sealed containercontaining one or more unused contact lenses immersed in an aqueouspackaging solution according to the present invention.

In one embodiment, the steps leading to the present packaging systemincludes (1) molding a biomedical device in a mold comprising at least afirst and second mold portion, (2) hydrating and cleaning the biomedicaldevice in a container comprising at least one of the mold portions, (3)introducing the packaging solution with the grafted glycosaminoglycanpolymers and/or crosslinked polymeric networks into the container withthe biomedical device supported therein, and (4) sealing the container.In one embodiment, the method also includes the step of sterilizing thecontents of the container. Sterilization may take place prior to, ormost conveniently after, sealing of the container and may be effected byany suitable method known in the art, e.g., by steam sterilizing orautoclaving of the sealed container at temperatures of, for example,about 120° C. or higher.

In another embodiment, the one or more grafted glycosaminoglycanpolymers and/or one or more crosslinked polymeric networks disclosedherein can be used in a gel formulation. As will be readily beunderstood by those skilled in the field of formulations, a gel issemisolid, suspension-type systems. Accordingly, in one embodiment, agel formulation can include one or more of the grafted glycosaminoglycanpolymers and/or one or more of the crosslinked polymeric networks andone or more gel forming agents. Gel forming agents for use herein can beany gelling agent typically used in the art for semi solid gel dosageforms. As used herein, the term “gelling agent” is intended to mean acompound used to render a liquid vehicle into a jelly-like vehicle.Exemplary gelling agents include, by way of example and withoutlimitation, synthetic macromolecules, cellulose derivatives (e.g.carboxymethylcellulose and hydroxypropylmethyl-cellulose) and naturalgums (e.g. tragacanth). The synthetic macromolecules include carbomers(e.g., Carbomer 910, 934, 934P, 940, 941, and 1342), which are highmolecular weight water-soluble polymers of acrylic acid crosslinked withallyl ethers of sucrose and/or pentaerythritol. Carbomers have differentviscosities depending on their polymeric composition. Gelling agents maybe selected from any of synthetic or semi-synthetic polymeric materials,polyacrylate copolymers, cellulose derivatives and polymethyl vinylether/maleic anhydride copolymers. Various grades of Carbopol such as,for example, Carbopol 934, 940, 941, 974, 980, 981, 1342, 5984, ETD2020,ETD 2050, and Ultrez 10 (available from Noveon of Cleveland, Ohio) canbe used in the present invention. The gel composition can includeCarbopol 980 as a gelling agent. A Carbopol is a carbomer. Generally,carbomers are synthetic high molecular weight polymer of acrylic acidthat are cross linked with either allylsucrose or allylethers ofpentaerythritol.

The gelation mechanism depends on neutralization of the carboxylic acidmoiety to form a soluble salt. The polymer is hydrophilic and producessparkling clear gels when neutralized. Carbomer gels possess goodthermal stability in that gel viscosity and yield value are essentiallyunaffected by temperature. As a topical product, carbomer gels possessoptimum rheological properties. The inherent pseudo plastic flow permitsimmediate recovery of viscosity when shear is terminated and the highyield value and quick break make it ideal for dispensing. In the presentpharmaceutical formulations, carbomer gels are used as a suspending orviscosity increasing agent. An aqueous solution of Carbopol is acidic innature due to the presence of free carboxylic acid residues.Neutralization of this solution crosslinks and gelatinizes the polymerto form a viscous integral structure of desired viscosity. The amount ofa gelling agent varies widely and will ordinarily range from about 0.1%to about 10% w/w.

The gel compositions can be incorporated into wound dressings (e.g.,bandages, adhesive bandages, transdermal patches). Generally, in theseembodiments, the gel compositions are embedded within puffs, gauzes,fleeces, gels, powders, sponges, or other materials that are associatedwith a second layer to form a wound dressing. Absorption enhancers canalso be used to increase the flux of the composition, and particularlythe therapeutic protein within the composition, across the skin. Therate of such flux can be controlled by either providing a ratecontrolling membrane or dispersing the therapeutic protein in a polymermatrix or gel.

In particular embodiments, the second layer of a wound dressing can bean elastomeric layer, vapor-permeable film, waterproof film, a woven ornonwoven fabric, mesh, or the like. The composition containing layer andsecond layer can be bonded using any suitable method, e.g., theapplication of adhesives, such as pressure sensitive adhesives, hot meltadhesives, curable adhesives; the application of heat or pressure, suchas in lamination; a physical attachment through the use of stitching,studs, other fasteners; or the like.

Wound dressings may include adhesives for attachment to the skin orother tissue. Although any adhesive suitable for forming a bond with theskin or other tissue can be used, in certain embodiments a pressuresensitive adhesive is used. Pressure sensitive adhesives are generallydefined as adhesives that adhere to a substrate when a light pressure isapplied but leave little to no residue when removed. Pressure sensitiveadhesives include solvent in solution adhesives, hot melt adhesives,aqueous emulsion adhesives, calenderable adhesives, and radiationcurable adhesives.

The most commonly used elastomers in pressure sensitive adhesives caninclude natural rubbers, styrene-butadiene latexes, polyisobutylene,butyl rubbers, acrylics, and silicones.

In illustrative embodiments, acrylic polymer or silicone-based pressuresensitive adhesives can be used. Acrylic polymers can often have a lowlevel of allergenicity, be cleanly removable from skin, possess a lowodor, and exhibit low rates of mechanical and chemical irritation.Medical grade silicone pressure sensitive adhesives can be chosen fortheir biocompatibility.

Amongst the factors that influence the suitability of a pressuresensitive adhesive for use in wound dressings of particular embodimentsis the absence of skin irritating components, sufficient cohesivestrength such that the adhesive can be cleanly removed from the skin,ability to accommodate skin movement without excessive mechanical skinirritation, and good resistance to body fluids.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative. The examples shouldnot be read as limiting the scope of the invention as defined in theclaims.

Example 1

Preparation of a PEGylated hyaluronic acid (HA) (48 kDa HA) using2-(2-aminoethoxy) ethanol following the general reaction scheme:

where n is 50 to 1000.

To a 1 L 3-neck flask with a 3.5 inch prop blade and overhead stirrerwas added 5.00 g of HA (12.4 mmol based on molecular weight (Mw) of403.31 for disaccharide unit) (48 kDa) and 495 mL deionized (DI) water.The mixture was stirred for 4 hours to ensure complete dissolution andprovide a clear solution having a pH of approximately 6.5. After 4hours, the pH was adjusted to 5.02 using 1N hydrochloric acid. To thesolution was added 1.484 g (12.9 mmol, 104 mole % based on Mw ofdisaccharide unit) of N-hydroxysuccinimide (NHS), in 5 ml DI water.Next, 2.377 g, (12.4 mmol, 100 mole % based on disaccharide unit) ofDimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) was added in5 mL of DI water. After 30 minutes activation, 1.356 g of2-(2-aminoethoxy) ethanol (PEG-2) (12.9 mmol, 104 mole % based ondisaccharide unit) was added, pre-dissolved in 5 mL DI water. Thereaction was allowed to proceed at room temperature for 24 hours. After24 hours, the solution was stirred in the presence of Amberlite IR 120Na⁺ form resin at 0.35 g resin for every gram of the 1 wt. % solution offunctionalized hyaluronate for 1 hour. After vacuum filtration to removethe resin, the solution was placed in 12,000-14,000 molecular weightcutoff (MWCO) dialysis bags. These bags were stirred in 5 mM phosphatebuffer pH 7.4 with 100 mM NaCl for 4 hours, followed by 18 hours in 5 mMphosphate buffer pH 7.4 with 50 mM NaCl, followed by 2 days with acontinuous flow of DI water. Following dialysis, the solution waslyophilized to yield 5 g of the product of Example 1.

Analysis by size exclusion chromatography (SEC-MALS) of dialyzedmaterial, i.e., final product, indicated a weight average molecularweight of 44,095 Da. Characterization of the material was carried out bysize exclusion chromatography, NMR, and high-resolution LC-MS ofenzymatically digested byproducts.

Example 2

Preparation of a PEGylated hyaluronic acid (1.2 MDa HA) using2-(2-aminoethoxy) ethanol following the general reaction scheme:

where n is 100 to 10,000.

To a 1 L round bottom flask fitted with 3.5 inch prop-blade and overheadstirrer was added 495 mL of DI water and 5.00 g of HA (1.2 MDa, 12.4mmol based on MW of 403.31 for disaccharide unit). The solution was thenstirred for 22 hours to ensure complete dissolution of materials andprovide a clear solution having a pH of approximately 6.5. The pH of thesolution was adjusted to 5.00 with 1N solution of hydrochloric acid. Tothe solution was added 0.314 g (2.73 mmol, 22 mole % based on Mw ofdisaccharide unit), N-hydroxysuccinimide (NHS), in 5 ml DI water. Next,0.475 g (2.48 mmol, 20 mole % based on disaccharide unit) ofDimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) was added tothe solution in 5 mL of DI water. After 2 hours the pH was at 5.05 when0.29 g of 2-(2-aminoethoxy) ethanol (PEG-2) (2.73 mmol, 22 mole % basedon Mw of disaccharide units) in 5 mL of DI water was added. The pH roseto 7.78 with that addition. The reaction mixture was then stirred for anadditional 16 hours and the pH dropped to 7.07.

The solution was then dialyzed using 12000-14000 MWCO RC (RegeneratedCellulose) membranes in 5 mM PBS buffer pH 7.4 with 100 mM NaCl for thefirst bath for three hours. The bath was exchanged for 5 mM PBS bufferpH 7.4 with 50 mM NaCl for another 3 hours. The bath was then exchangedto DI water only overnight. The next day dialysis was continued with acontinuous flow of DI water for 8 hours for the fourth bath, thenallowed to sit overnight in DI water for the fifth bath. The next daydialysis was continued with continuous flow DI water for 8 hours for thesixth bath. Then the solution was stirred in the presence of AmberliteIR 120 Na⁺ form resin at 0.35 g resin for every gram of the 1 wt. %solution of PEG functionalized hyaluronate for 1.5 hours. The materialwas lyophilized for 3 days to give 3.8 g (74% yield) of a fibrousmaterial.

Analysis by size exclusion chromatography of the final product indicateda weight average molecular weight of 1,225,139 Da. Characterization ofthe material was carried out by size exclusion chromatography, NMR, andhigh-resolution LC-MS of enzymatically digested byproducts.

Example 3

Preparation of a covalently crosslinked network of PEG-functionalizedhyaluronic acid with 1,4-butanediol diglycidyl ether (BDDE) followingthe general reaction scheme:

where n is 50 to 10,000 and n₁ is 1 to 10,000.

0.5 g of the PEG-functionalized HA (2.056 mmol based on MW of 486.40 fordisaccharide unit) of Example 1 above was dissolved in DI water at 0.5wt. % and allowed to stir for 22 hours at 300 RPM to ensure completedissolution of material. The pH was adjusted to 12 using 1N sodiumhydroxide and then 0.212 g of BDDE (1.049 mmol, 102 mole % based ondisaccharide unit) was added and allowed to stir at 500 RPM for 24hours. The reaction mixture was then poured into an excess of ethanol.The precipitate which formed was filtered and washed 3 times withethanol then dried under vacuum for an additional 24 hours.Characterization of the material was carried out by size exclusionchromatography. The reaction produced the following products 1-4:

where n is as defined above.

Example 4

Preparation of a covalently crosslinked network of PEG-functionalizedhyaluronic acid with BDDE following the general reaction scheme:

where n is 50 to 10,000 and n₁ is 1 to 10,000.

0.5 g of the PEG-functionalized HA (2.056 mmol based on MW of 486.40 fordisaccharide unit) of Example 2 was dissolved in DI water at 0.5 wt. %and allowed to stir for 22 hours at 300 RPM to ensure completedissolution of material. The pH was adjusted to 12 using 1N sodiumhydroxide and then 0.212 g of BDDE (1.049 mmol, 102 mole % based ondisaccharide unit) was added and allowed to stir at 500 RPM for 24hours. The reaction mixture was then poured into an excess of ethanol.The precipitate which formed was filtered and washed 3 times withethanol then dried under vacuum for an additional 24 hours. The reactionproduced products 1-4 as shown in Example 3. Characterization of thematerial was carried out by size exclusion chromatography.

Example 5

Preparation of a PEGylated hyaluronic acid (1.2 MDa HA) using mPEG-NH₂500 (Methoxypolyethylene glycol amine 550) following the generalreaction scheme:

where n is 25 to 10,000.

To a 1 L round bottom flask equipped with a 3.5 inch prop-blade andoverhead stirrer was added 400 mL of DI water and 5.00 g of HA (1.2 MDa,12.4 mmol based on MW of 403.31 for disaccharide unit). The solution wasthen stirred for 16 hours to ensure complete dissolution of materialsand provide a clear solution having a pH of approximately 6.5. To thesolution was added 0.22 g (1.92 mmol, 15.5 mole % based on Mw ofdisaccharide unit) of N-hydroxysuccinimide (NHS), in 5 mL dimethylsulphoxide (DMSO). Next, 0.36 g (1.88 mmol, 15.2 mole % based ondisaccharide unit) of Dimethylaminopropyl-N-ethylcarbodiimidehydrochloride (EDC) in 5 mL of DI water was added. After 10 minutes 0.68g of m-PEG-NH₂ (1.24 mmol, 10 mole % based on Mw of disaccharide unit)in 5 mL of DI water was added. The remaining 70 mL DI water was added tomake a 1 wt. % solution of HA· resulting in a solution with a pH of 6.3.The pH was increased to 6.4 with the addition of 0.25N NaOH and thereaction was continued for 24 hours.

The reaction product was filtered using a cloth filter to remove anyimpurities and insoluble material. The reaction product was thenprecipitated in 4000 mL acetone under constant stirring by slowly addingthe reaction product using a liquid addition funnel. The precipitate wasfurther dissolved in DI water (400 mL) under constant stirring. Oncomplete dissolution, the precipitation as earlier described wasrepeated 2 times (overall 3 precipitations). The residue was dried for 8hours at 35° C. under high vacuum.

Example 6

The reaction scheme of Example 5 was repeated except HA (35 kDa) wasused with mPEG-NH₂ (550) to provide the structure set forth in Example5.

Example 7

A packaging solution is made by mixing the following components in therespective amounts listed in Table 1.

TABLE 1 Ingredients Parts Monobasic sodium phosphate monohydrate 0.015Dibasic sodium phosphate anhydrous 0.065 Sodium Chloride 0.900 PurifiedWater, USP 99.020 Functionalized HA of Example 1, 2, 3, 4, 5 or 6 0.010to 1.000 pH 6.0 to 8.0 Osmolality 200 to 400

Example 8

A packaging solution is made by mixing the following components in therespective amounts listed in Table 2.

TABLE 2 Ingredients Parts Monobasic sodium phosphate monohydrate 0.015Dibasic sodium phosphate anhydrous 0.065 Sodium Chloride 0.900Poloxamine 1107 0.500 Purified Water, USP 98.520  Functionalized HA ofExample 1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 6.0 to 8.0 Osmolality 200to 400

Example 9

A packaging solution is made by mixing the following components in therespective amounts listed in Table 3.

TABLE 3 Ingredients Parts Monobasic sodium phosphate monohydrate 0.015Dibasic sodium phosphate anhydrous 0.066 Sodium Chloride 0.633Poloxamine 1107 0.505 Glycerol 1.015 Purified Water, USP 98.520 Functionalized HA of Example 1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 6.0 to8.0 Osmolality 200 to 400

Example 10

A packaging solution is made by mixing the following components in therespective amounts listed in Table 4.

TABLE 4 Ingredients Parts Monobasic sodium phosphate monohydrate 0.00925Dibasic sodium phosphate anhydrous 0.032   Potassium Chloride 0.700  Poloxamine 1107 0.550   Poloxamer 181 0.02    Glycerol 0.900   ComfortAgents 0.010 to 5.000 Purified Water, USP 96.889    Functionalized HA ofExample 1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 6.0 to 8.0 Osmolality 200to 400

Example 11

A packaging solution is made by mixing the following components in therespective amounts listed in Table 5.

TABLE 5 Ingredients Parts Monobasic sodium phosphate monohydrate 0.05188Dibasic sodium phosphate anhydrous 0.1893  Potassium Chloride 0.3855 Poloxamine 1107 0.550   Poloxamer 181 0.02    Glycerol 0.900   ComfortAgents 0.010 to 5.000 Purified Water, USP 97.027    Functionalized HA ofExample 1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 6.0 to 8.0 Osmolality 200to 400

Example 12

A packaging solution is made by mixing the following components in therespective amounts listed in Table 6.

TABLE 6 Ingredients Parts Trizma HCl 0.627 Trizma Base 0.116 SodiumChloride 0.577 Purified Water, USP 98.680 Functionalized HA of Example1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 3.0 to 6.2 Osmolality 200 to 400

Example 13

A packaging solution is made by mixing the following components in therespective amounts listed in Table 7.

TABLE 7 Ingredients Parts Trizma HCl 0.627 Trizma Base 0.116 SodiumChloride 0.577 Purified Water, USP 98.680 Functionalized HA of Example1, 2, 3, 4, 5 or 6 0.010 to 1.000 Comfort Agents 0.010 to 5.000 pH 3.0to 6.2 Osmolality 200 to 400

Example 14

A packaging solution is made by mixing the following components in therespective amounts listed in Table 8.

TABLE 8 Ingredients Parts Citric Acid, Anhydrous 11.320 Sodium Citrate62.220 Sodium Chloride 26.460 Purified Water, USP 100.000 FunctionalizedHA of Example 1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 3.0 to 6.2 Osmolality200 to 400

Example 15

A packaging solution is made by mixing the following components in therespective amounts listed in Table 9.

TABLE 9 Ingredients Parts Citric Acid, Anhydrous 11.320 Sodium Citrate62.220 Sodium Chloride 26.460 Purified Water, USP 100.000 FunctionalizedHA of Example 1, 2, 3, 4, 5 or 6 0.010 to 1.000 Comfort Agents 0.010 to5.000 pH 3.0 to 6.2 Osmolality 200 to 400

Example 16

A packaging solution is made by mixing the following components in therespective amounts listed in Table 10.

TABLE 10 Ingredients Parts MOPS Sodium Salt 0.560 MOPS or3-(N-morpholino)propanesulfonic acid 0.520 Sodium Chloride 0.630Purified Water, USP 98.280 Functionalized HA of Example 1, 2, 3, 4, 5 or6 0.010 to 1.000 pH 6.5 to 7.9 Osmolality 200 to 400

Example 17

A packaging solution is made by mixing the following components in therespective amounts listed in Table 11.

TABLE 11 Ingredients Parts MOPS Sodium Salt 0.560 MOPS or3-(N-morpholino)propane sulfonic acid 0.520 Sodium Chloride 0.630Purified Water, USP 98.280  Functionalized HA of Example 1, 2, 3, 4, 5or 6 0.010 to 1.000 Comfort Agents 0.010 to 5.000 pH 6.5 to 7.9Osmolality 200 to 400

Example 18

A packaging solution is made by mixing the following components in therespective amounts listed in Table 12.

TABLE 12 Ingredients Parts Sodium Borate 0.610 Boric Acid 0.098 SodiumChloride 0.886 Purified Water, USP 98.406 Functionalized HA of Example1, 2, 3, 4, 5 or 6 0.010 to 1.000 pH 7.0 to 9.0 Osmolality 200 to 400

Example 19

A packaging solution was made by mixing the following components in therespective amounts listed in Table 13.

TABLE 13 Ingredients Parts Sodium Borate 0.610 Boric Acid 0.098 SodiumChloride 0.886 Purified Water, USP 98.406 Functionalized HA of Example1, 2, 3, 4, 5 or 6 0.010 to 1.000 Comfort Agents 0.010 to 5.000 pH 7.0to 9.0 Osmolality 200 to 400

Example 20

A packaging solution was made by mixing the following components in therespective amounts listed in Table 14.

TABLE 14 Ingredients Parts Monobasic sodium phosphate monohydrate 0.015Dibasic sodium phosphate anhydrous 0.065 Sodium Chloride 0.900 PurifiedWater, USP 99.020 Functionalized HA of Example 2 0.020 pH 7.28Osmolality 305

Example 21

A packaging solution was made by mixing the following components in therespective amounts listed in Table 15.

TABLE 15 Ingredients Parts Monobasic sodium phosphate monohydrate0.00925 Dibasic sodium phosphate anhydrous 0.032 Potassium Chloride0.700 Poloxamine 1107 0.550 Poloxamer 181 0.02 Glycerol 0.900 Erythritol0.900 Purified Water, USP 96.889 Functionalized HA of Example 2 0.020 pH7.4 Osmolality 370

Example 22

Autoclave degradation was studied for HA-2PEG and did not show anystatistically significant changes in pH, viscosity and osmolality evenafter 2 autoclave cycles as shown below in Table 16.

TABLE 16 Properties Condition Example 21 Example 20 pH 0× autoclave 7.427.26 1× autoclave 7.41 7.29 2× autoclave 7.41 7.29 Osmolarity 0×autoclave 323 294 1× autoclave 319 298 2× autoclave 323 300 Viscosity 0×autoclave 1.67 1.07 1× autoclave 1.50 1.13 2× autoclave 1.44 1.07Molecular Weight 0× autoclave 1,440,000 1,105,000 (Daltons) 1× autoclave800,000 121,400 2× autoclave 600,000 54,540

Example 23

Contact lenses made of Balafilcon A were cast and processed understandard manufacturing procedures. Balafilcon A is a copolymer comprisedof 3-[tris(tri-methylsiloxy)silyl] propyl vinyl carbamate,N-vinyl-2-pyrrolidone (NVP),1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane andN-vinyloxycarbonyl alanine. All Balafilcon A lenses were air-plasmatreated prior to exposure to the crosslinked polymeric network.

For coating with the grafted polymer of Example 1, each lens was placedin a polypropylene blister package containing 3.8 mL of a 100 or 250 ppm(w/v) solution of the grafted polymer dissolved in an appropriate buffersystem, e.g., a phosphate-buffered saline system (PBS), aborate-buffered saline (BBS) with or without containing 300 ppm EDTA.The blister packages were sealed with foil lidstock and autoclaved at121° C. for 30 minutes.

Example 24

Contact lenses made of Balafilcon A are cast and processed understandard manufacturing procedures. Balafilcon A is a copolymer comprisedof 3-[tris(tri-methylsiloxy)silyl] propyl vinyl carbamate,N-vinyl-2-pyrrolidone (NVP),1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]polydimethylsiloxane andN-vinyloxycarbonyl alanine. All Balafilcon A lenses were air-plasmatreated prior to exposure to the crosslinked polymeric network.

For coating with the grafted polymer of Example 2, each lens is placedin a polypropylene blister package containing 3.8 mL of a 100 or 250 ppm(w/v) solution of the grafted polymer dissolved in an appropriate buffersystem, e.g., a PBS, a BBS with or without containing 300 ppm EDTA. Theblister packages were sealed with foil lidstock and autoclaved at 121°C. for 30 minutes.

Example 25

Preparation of in situ PEG-functionalization of hyaluronic acid (48 kDaHA) following the general reaction scheme:

To a 1 L 3-neck flask with a 3.5 inch prop blade and overhead stirrer isadded 5.00 g of HA (12.4 mmol based on molecular weight (Mw) of 403.31for disaccharide unit) (48 kDa) and 495 mL deionized (DI) water. Themixture is stirred for 4 hours to ensure complete dissolution andprovide a clear solution having a pH of approximately 6.5. After 4hours, the pH is adjusted to 5.02 using 1N hydrochloric acid. To thesolution is added 1.484 g (12.9 mmol, 104 mole % based on Mw ofdisaccharide unit) of N-hydroxysuccinimide (NHS), in 5 ml DI water.Next, 2.377 g, (12.4 mmol, 100 mole % based on disaccharide unit) ofDimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) is added in5 mL of DI water. After 30 minutes activation, 0.906 g ofepoxypropylamine (12.4 mmol, 100 mole % based on disaccharide unit) wasadded, pre-dissolved in 5 mL DI water. The reaction is allowed toproceed at room temperature for 24 hours.

After 24 hours, the pH is adjusted to 8 using 1N NaOH. 0.77 g ethyleneglycol (12.4 mmol, 100 mole % based on disaccharide unit) is added,pre-dissolved in 5 mL DI water. The reaction was allowed to proceed atroom temperature for 4 hours. After 4 hours, 0.919 g glycidol (12.4mmol, 100 mole % based on disaccharide unit) is added, pre-dissolved in5 mL DI water. The reaction is allowed to proceed at room temperaturefor 24 hours. After 24 hours, the solution is placed in 12,000 to 14,000molecular weight cutoff (MWCO) dialysis bags. These bags are stirred in5 mM phosphate buffer pH 7.4 with 100 mM NaCl for 4 hours, followed by18 hours in 5 mM phosphate buffer pH 7.4 with 50 mM NaCl, followed by 2days with a continuous flow of DI water. Following dialysis, thesolution is stirred in the presence of Amberlite IR 120 Na⁺ form resinat 0.35 g resin for every gram of the 1 wt. % solution of functionalizedhyaluronate for 1.5 hours. After vacuum filtration to remove the resin,the solution is lyophilized to yield 5 g of product.

Characterization of the product is carried out by size exclusionchromatography, NMR, and high-resolution LC-MS of enzymatically digestedbyproducts.

Example 26

Preparation of in situ PEG-functionalization of hyaluronic acid (1.2 MDaHA) following the general reaction scheme:

To a 1 L 3-neck flask with a 3.5 inch prop blade and overhead stirrer isadded 5.00 g of HA (12.4 mmol based on molecular weight (Mw) of 403.31for disaccharide unit) (1.2 MDa) and 495 mL deionized (DI) water. Themixture is stirred for 4 hours to ensure complete dissolution andprovide a clear solution having a pH of approximately 6.5. After 4hours, the pH is adjusted to 5.02 using 1N hydrochloric acid. To thesolution is added 1.484 g (12.9 mmol, 104 mole % based on Mw ofdisaccharide unit) of N-hydroxysuccinimide (NHS), in 5 ml DI water.Next, 2.377 g, (12.4 mmol, 100 mole % based on disaccharide unit) ofDimethylaminopropyl-N-ethylcarbodiimide hydrochloride (EDC) is added in5 mL of DI water. After 30 minutes activation, 0.906 g ofepoxypropylamine (12.4 mmol, 100 mole % based on disaccharide unit) isadded, pre-dissolved in 5 mL DI water. The reaction is allowed toproceed at room temperature for 24 hours.

After 24 hours, the pH is adjusted to 8 using 1N NaOH. Next, 0.77 gethylene glycol (12.4 mmol, 100 mole % based on disaccharide unit) isadded, pre-dissolved in 5 mL DI water. The reaction is allowed toproceed at room temperature for 4 hours. After 4 hours, 0.919 g glycidol(12.4 mmol, 100 mole % based on disaccharide unit) is added,pre-dissolved in 5 mL DI water. The reaction is allowed to proceed atroom temperature for 24 hours. After 24 hours, the solution is placed in12,000 to 14,000 molecular weight cutoff (MWCO) dialysis bags. Thesebags are stirred in 5 mM phosphate buffer pH 7.4 with 100 mM NaCl for 4hours, followed by 18 hours in 5 mM phosphate buffer pH 7.4 with 50 mMNaCl, followed by 2 days with a continuous flow of DI water. Followingdialysis, the solution is stirred in the presence of Amberlite IR 120Na⁺ form resin at 0.35 g resin for every gram of the 1 wt. % solution offunctionalized hyaluronate for 1.5 hours. After vacuum filtration toremove the resin, the solution is lyophilized to yield 5 g of theproduct.

Characterization is carried out by size exclusion chromatography, NMR,and high-resolution LC-MS of enzymatically digested byproducts.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplifications ofpreferred embodiments. For example, the functions described above andimplemented as the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of the featuresand advantages appended hereto.

What is claimed is:
 1. A crosslinked polymeric network comprising areaction product comprising a grafted glycosaminoglycan polymercomprising a glycosaminoglycan having a polymer backbone and one or moreside chains comprising a polyalkylene glycol-containing residue graftedonto the polymer backbone, and one or more crosslinking agents.
 2. Thecrosslinked polymeric network according to claim 1, wherein theglycosaminoglycan is selected from the group consisting of chondroitin,chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparansulfate, heparosan, hyaluronan, hyaluronic acid or a salt thereof,sucrose, lactulose, lactose, maltose, trehalose, cellobiose, mannobiose,chitobiose, chitosan and cellulose, and the polyalkyleneglycol-containing residue is derived from a polymer or a salt thereofhaving the following structure:Z—(((CH₂)_(a)—O)_(b))_(c)—Y wherein Z is a reactive or non-reactiveend-capped group, Y is reactive functional end group, a is from 2 to 6,b is from 2 to 10,000 and c is 1 or
 2. 3. The crosslinked polymericnetwork according to claim 1, wherein the one or more crosslinkingagents are a bi- or polyfunctional crosslinking agent comprising two ormore reactive functional groups.
 4. The crosslinked polymeric networkaccording to claim 1, having a weight average molecular weight rangingfrom about 20,000 to about 6,000,000 Daltons (Da).
 5. A biomedicaldevice having a coating on a surface thereof, the coating comprising agrafted glycosaminoglycan polymer comprising a glycosaminoglycan havinga polymer backbone and one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the polymer backbone.
 6. Thebiomedical device according to claim 5, wherein the one or moreglycosaminoglycans are selected from the group consisting ofchondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin,heparan sulfate, hyaluronan, and hyaluronic acid or a salt thereof. 7.The biomedical device according to claim 5, wherein the polyalkyleneglycol-containing residue is derived from a polymer or a salt thereofhaving the following structure:Z—(((CH₂)_(a)—O)_(b))_(c)—Y wherein Z is a reactive or non-reactiveend-capped group, Y is reactive functional end group, a is from 2 to 6,b is from 2 to 10,000 and c is 1 or
 2. 8. The biomedical deviceaccording to claim 7, wherein Z is selected from the group consisting ofan alkoxy group, a hydroxyl group, a glycidyl group, a thiol group andan amine group, and Y is selected from the group consisting of —X—NH₂,—X— polydimethylsiloxane-NH₂, —X—SH, and —X—C(O)—R′ wherein X is alinker group and R′ is hydrogen or an organic moiety comprised of 1 to20 carbon atoms.
 9. The biomedical device according to claim 5, whereinthe biomedical device is a contact lens or an intraocular lens.
 10. Apackaging system for the storage of an ophthalmic device comprising asealed container containing one or more unused ophthalmic devicesimmersed in an aqueous packaging solution comprising a graftedglycosaminoglycan polymer comprising a glycosaminoglycan having apolymer backbone and one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the polymer backbone, wherein theaqueous packaging solution has an osmolality of at least about 200mOsm/kg, a pH of about 6 to about 9 and is sterilized.
 11. The packagingsystem according to claim 10, wherein the polyalkylene glycol-containingresidue is derived from a polymer or a salt thereof having the followingstructure:Z—(((CH₂)_(a)—O)_(b))_(c)—Y wherein Z is a reactive or non-reactiveend-capped group, Y is reactive functional end group, a is from 2 to 6,b is from 2 to 10,000 and c is 1 or
 2. 12. The packaging systemaccording to claim 11, wherein Z is selected from the group consistingof an alkoxy group, a hydroxyl group, a glycidyl group, a thiol groupand an amine group, and Y is selected from the group consisting of—X—NH₂, —X— polydimethylsiloxane-NH₂, —X—SH, and —X—C(O)—R′ wherein X isa linker group and R′ is hydrogen or an organic moiety comprised of 1 to20 carbon atoms.
 13. The packaging system according to claim 10, whereinthe grafted glycosaminoglycan polymer is a reaction product of (a) aglycosaminoglycan having a polymer backbone containing reactivefunctionalities; and (b) a polymer comprising polyalkylene glycol chainsand at least one reactive end group complementary to at least one of thereactive functionalities of the polymer backbone of theglycosaminoglycan; wherein the at least one reactive end group of thepolymer forms one or more side chains comprising a polyalkyleneglycol-containing residue grafted onto the at least one of the reactivefunctionalities of the polymer backbone of the glycosaminoglycan,wherein the reaction product is derived from (i) activating theglycosaminoglycan in a solution comprising one or more catalysts with anactivator comprising one or more epoxyamines; and (ii) grafting the oneor more side chains comprising the polyalkylene glycol-containingresidue onto the at least one of the reactive functionalities of thepolymer backbone of the glycosaminoglycan by sequentially orsimultaneously adding a polyol and an epoxyalcohol to the activatedglycosaminoglycan.
 14. The packaging system according to claim 13,wherein the one or more epoxyamines include both at least one aminemoiety and at least one epoxide moiety.
 15. The packaging systemaccording to claim 10, wherein the grafted glycosaminoglycan polymer iscrosslinked with one or more crosslinking agents.
 16. The packagingsystem according to claim 15, wherein the one or more crosslinkingagents are a bi- or polyfunctional crosslinking agent comprising two ormore reactive functional groups.
 17. The packaging system according toclaim 10, wherein the aqueous packaging solution further comprises oneor more comfort agents.
 18. A method of preparing a package comprising astorable, sterile ophthalmic device, the method comprising: (a)immersing an ophthalmic device in an aqueous packaging solutioncomprising a grafted glycosaminoglycan polymer comprising aglycosaminoglycan having a polymer backbone and one or more side chainscomprising a polyalkylene glycol-containing residue grafted onto thepolymer backbone, wherein the solution has an osmolality of at leastabout 200 mOsm/kg and a pH in the range of about 6 to about 9; (b)packaging the aqueous packaging solution and the ophthalmic device in amanner preventing contamination of the ophthalmic device bymicroorganisms; and (c) sterilizing the packaged aqueous packagingsolution and the ophthalmic device.
 19. A gel composition for promotingwound healing, wherein the gel composition comprises one or more of thecrosslinked polymeric networks according to claim
 1. 20. A wounddressing comprising the gel composition according to claim 19.